Chemokine-chemokine receptor axis: Emerging immunotherapeutic paradigms for solid tumor microenvironment reprogramming.

Chemokine–chemokine receptor axis: Emerging immunotherapeutic paradigms for solid tumor microenvironment reprogramming - PMC Skip to main content An official website of the United States government Here's how you know Here's how you know Official websites use .gov A .gov website belongs to an official government organization in the United States. Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites. Search Log in Dashboard Publications Account settings Log out Search… Search NCBI Primary site navigation Search Logged in as: Dashboard Publications Account settings Log in Search PMC Full-Text Archive Search in PMC Journal List User Guide PERMALINK Copy As a library, NLM provides access to scientific literature. Inclusion in an NLM database does not imply endorsement of, or agreement with, the contents by NLM or the National Institutes of Health. Learn more: PMC Disclaimer | PMC Copyright Notice Chin Med J (Engl) . 2026 Mar 11;139(8):1125–1148. doi: 10.1097/CM9.0000000000004009 Search in PMC Search in PubMed View in NLM Catalog Add to search Chemokine–chemokine receptor axis: Emerging immunotherapeutic paradigms for solid tumor microenvironment reprogramming Yang Zhao Yang Zhao 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 2 Institute of Cell and Gene Technology, Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China Find articles by Yang Zhao 1, 2 , Xueqian Wang Xueqian Wang 3 Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518107, China 4 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China Find articles by Xueqian Wang 3, 4 , Tong Lei Tong Lei 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 2 Institute of Cell and Gene Technology, Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China Find articles by Tong Lei 1, 2 , Hezhe Lu Hezhe Lu 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 2 Institute of Cell and Gene Technology, Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China Find articles by Hezhe Lu 1, 2, ✉ , Yong Zhao Yong Zhao 3 Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518107, China 4 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China Find articles by Yong Zhao 3, 4, ✉ , Guiying Wang Guiying Wang 5 General Surgery Department, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China 6 General Surgery Department, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China Find articles by Guiying Wang 5, 6, ✉ Editor: Yanjie Yin Author information Article notes Copyright and License information 1 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China 2 Institute of Cell and Gene Technology, Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China 3 Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518107, China 4 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China 5 General Surgery Department, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China 6 General Surgery Department, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, China ✉ Correspondence to: Yong Zhao, Institute of Cell and Gene Technology, Faculty of Synthetic Biology, Shenzhen University of Advanced Technology, Shenzhen, Guangdong 518107, China; Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China E-Mail: [email protected] ; ✉ Hezhe Lu, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Datun Road 1-3, Chaoyang District, Beijing 100101, China E-Mail: [email protected] ; ✉ Guiying Wang, General Surgery Department, the Second Hospital of Hebei Medical University, 215 Heping West Road, Shijiazhuang, Hebei 050000, China. General Surgery Department, the Fourth Hospital of Hebei Medical University, 12 Jiankang Road, Shijiazhuang, Hebei 050011, China E-Mail: [email protected] Received 2025 Oct 16; Issue date 2026 Apr 20. Copyright © 2026 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND) , where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMC Copyright notice PMCID: PMC13090073  PMID: 41813655 Abstract Chemokines play a critical role in regulating immune cell infiltration and their interactions with cancer cells in the tumor microenvironment (TME). Disrupted chemokine gradients influence immune cell recruitment and activation, as well as tumor cell proliferation, metastasis, and angiogenesis. By modulating these processes, chemokines shape the immune landscape of the tumor microenvironment, driving either immunosuppressive or immunostimulatory responses with corresponding pro- or antitumor effects. Dysregulated expression of chemokines and their receptors is strongly associated with tumor initiation, progression, and clinical outcomes. As a result, the chemokine receptor axis has gained prominence as a therapeutic target in cancer immunotherapy. This review explores chemokine expression profiles across various tumor types and their receptor-mediated interactions with immune cells. It also summarizes current strategies to therapeutically target chemokine signaling, both as standalone interventions and in combination with other treatment modalities. Keywords: Chemokines, Chemokine receptors, Tumor microenvironment, Tumor immunotherapy Introduction Cancer progression is a complex, multistep process driven by coordinated interactions between immune and nonimmune cells, which collectively shape the tumor microenvironment (TME). This cellular interplay is governed by chemokines, small chemotactic cytokines that regulate cell migration through tightly controlled spatial and temporal expression. Chemokines are grouped into four subfamilies based on the arrangement of their N-terminal cysteine residues: Cysteine–Cysteine (C–C or CC), Cysteine–X–Cysteine (C–X–C or CXC), Cysteine–X3–Cysteine (C–X3–C or CXC), and X–Cysteine (X–C or XC) motif ligands. They primarily signal through G protein-coupled receptors, which span the cell membrane seven times. In parallel, chemokines also bind atypical chemokine receptors (ACKRs), which share a similar structure but lack G protein signaling capacity. Instead of inducing traditional signaling pathways, ACKRs regulate local chemokine levels by promoting their sequestration and degradation. To date, around 50 chemokines, 20 signaling G protein-coupled receptors, and 4 ACKRs have been identified. Although chemokines are involved in various nonimmune functions, they play essential roles in directing immune cell trafficking, activation, and communication. [ 1 ] Within the TME, chemokines contribute to both tumor-promoting and tumor-suppressive processes by modulating immune cell recruitment and behavior. Tumor and stromal cells secrete distinct chemokine profiles that attract specific immune subsets, shaping the immunological landscape and influencing disease outcomes. Given their central role in immune regulation and tumor progression, chemokine-receptor interactions have emerged as promising targets for cancer therapy. [ 2 ] Chemokines can directly affect tumor cells, drive immune infiltration, and regulate processes such as epithelial–mesenchymal transition. A deeper understanding of chemokine dynamics in cancer provides a critical framework for developing immunotherapies aimed at generating durable antitumor responses. This review examines the diverse roles of the chemokine–chemokine receptor axis in orchestrating immune cell migration within the TME and highlights ongoing preclinical and clinical efforts to exploit this pathway in cancer immunotherapy. Chemokine Expression Profiles and Functional Characteristics in Tumors Chemokines are secreted by a wide range of cells within the TME, including tumor cells, immune cells, and stromal components. Tumor cells originating from various tissues can produce chemokines with growth factor-like activity and tightly regulate their expression through transcriptional activation or repression. This production is shaped by the surrounding TME and modulated by diverse therapeutic interventions, such as growth factors, radiotherapy, chemotherapy, hypoxia, and adoptive immune cell therapies. [ 3 , 4 , 5 , 6 , 7 ] Interactions within the TME, particularly with cancer-associated fibroblasts (CAFs) and tumor-infiltrating immune cells, further influence chemokine expression. Regulation involves a complex interplay between external environmental cues and intrinsic genetic and epigenetic mechanisms. As a result, chemokine levels may be upregulated or downregulated depending on tumor type and context, reflecting a highly dynamic and context-dependent regulatory system. [ 7 , 8 , 9 ] Multiple nonmalignant cell populations significantly contribute to chemokine signaling within the TME. Tumor-associated macrophages (TAMs) predominantly release C–C motif ligand 2 (CCL2), CCL3, CCL4, CCL5, CCL17, CCL18, CCL22, CXCL8, and CXCL12. Myeloid-derived suppressor cells (MDSCs) secrete C–X–C motif ligand 1 (CXCL1), CXCL2, CXCL5, CXCL8, CCL2, CCL4, CCL5, and CXCL12. Tumor-associated neutrophils (TANs) express a similar chemokine profile, including CXCL1, CXCL2, CXCL5, CXCL8, CCL2, CCL3, CCL4, CCL5, and CXCL12. Mesenchymal stem cells produce CXCL12, CXCL8, CXCL1, CCL2, CCL5, CCL7, and CCL20, while CAFs secrete a comparable set of chemokines, including CXCL12, CXCL8, CXCL1, CXCL2, CXCL5, CCL2, CCL5, CCL7, and CCL20. These cells collectively contribute to pre-metastatic niche formation and actively shape tumor progression. [ 10 , 11 , 12 , 13 , 14 ] Chemokines play a central role in recruiting immunosuppressive cells, such as MDSCs, TAMs, TANs, and regulatory T cells (Tregs), which suppress antitumor immunity and foster an immunosuppressive TME conducive to metastasis. They also attract T-helper type 2 (Th2) cells and additional Tregs, further inhibiting cytotoxic T cell lymphocytes (CTL) activity, and mobilize TANs, which promote extracellular matrix (ECM) remodeling and angiogenesis. Through these mechanisms, chemokines help establish an immune-permissive niche even before tumor cells arrive, allowing circulating tumor cells to evade immune detection and elimination. The roles of chemokines in cancer are diverse and highly context-dependent. Many are detectable in plasma and in tissues such as the liver, spleen, colon, small intestine, and bone marrow, though notably absent in the brain and kidney. [ 15 ] Their tissue specificity and serum detectability support their utility as diagnostic biomarkers and prognostic indicators in several malignancies. [ 16 , 17 ] Functionally, chemokines exhibit both pro- and antitumor activities. Some enhance tumor survival by promoting resistance to apoptosis and contributing to drug resistance. [ 18 ] Others support antitumor immunity by recruiting CTLs and natural killer (NK) cells into the TME. [ 19 ] This functional duality highlights the complexity of chemokine signaling and underscores their potential as targets for therapeutic intervention in cancer. To understand the chemokine transcription profiles across tumor types, we conducted a systematic evaluation of all known human chemokines in diverse cancers [Supplementary Figure 1, http://links.lww.com/CM9/C797 ]. Expression data were sourced from The Cancer Genome Atlas (TCGA) and the Genotype–Tissue Expression project, with patient and sample details summarized in Supplementary Table 1, http://links.lww.com/CM9/C797 . We compared chemokine mRNA levels between tumor and matched normal tissues across multiple cancer types [Supplementary Figure 2, http://links.lww.com/CM9/C797 ], calculating average fold changes to quantify differential expression. Consistent patterns of upregulation or downregulation were identified, providing a comprehensive overview of chemokine dysregulation in cancer. A comprehensive analysis of chemokine expression profiles revealed distinct tumor-associated signatures: (1) several chemokines, CCL18, CXCL7, CXCL5, CCL25, CXCL13, CXCL9, CXCL10, CXCL11, CCL1, and CCL17 were consistently overexpressed across a wide range of cancers. These chemokines are strongly linked to tertiary lymphoid structure (TLS) formation and lymphocyte infiltration. [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ] In contrast, CCL2, CCL14, CXCL12, CCL16, CXCL2, CXCL3, CXCL16, CX3C motif chemokine ligand 1 (CX3CL1), CXCL14, and CCL28 showed minimal or no differential expression in most tumor types. (2) CXCL17 was significantly downregulated in most cancers, with marked suppression in breast invasive carcinoma and thyroid carcinoma (THCA). However, it was notably upregulated in uterine corpus endometrial carcinoma (UCEC), suggesting a context-dependent role with potential diagnostic or therapeutic implications in UCEC that merits further investigation. (3) Several chemokines exhibited selective overexpression in specific tumor types. CCL18: stomach adenocarcinoma (STAD), skin cutaneous melanoma (SKCM), lower grade glioma, kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), pheochromocytoma and paraganglioma (PCPG), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney chromophobe, prostate adenocarcinoma (PRAD), glioblastoma multiforme, glioma, bladder urothelial carcinoma (BLCA), THCA, uterine carcinosarcoma (UCS); CXCL7: STAD, SKCM, pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma, colon adenocarcinoma, colon adenocarcinoma/rectum adenocarcinoma esophageal carcinoma, stomach and esophageal carcinoma (STES), BLCA; CXCL5: ovarian serous cystadenocarcinoma (OVCS), STAD, SKCM, pan-kidney cohort (KICH+KIRC+KIRP), KIRC, KIRP, PCPG, PAAD, UCEC, cholangiocarcinoma, STES, BLCA, adrenocortical carcinoma (ACC), esophageal carcinoma, THCA, UCS; CCL25: head and neck squamous cell carcinoma (HNSC), OVCS, CESC, kidney chromophobe, PRAD, PAAD, ACC, lung adenocarcinoma (LUAD), lung squamous cell carcinoma, Wilms tumor, esophageal carcinoma, liver hepatocellular carcinoma, UCS; CXCL13: HNSC, SKCM, KIRC, PCPG, CESC, cholangiocarcinoma, LUAD, lung squamous cell carcinoma, Wilms tumor; CXCL9, CXCL10, CXCL11: HNSC, OVCS, STAD, SKCM, breast invasive carcinoma , testicular germ cell tumors, KIRC, STES, BLCA, ACC, LUAD; CCL17: THCA, PRAD. These findings underscore the heterogeneity and tumor specificity of chemokine expression, emphasizing their potential roles in cancer progression. Further studies are needed to clarify their functional mechanisms and therapeutic relevance. Although some chemokines drive tumor progression, others support antitumor immunity or promote chemoresistance. To explore these roles, we examined tumor-to-normal expression ratios of experimentally validated pro-tumor [Figure 1 ] and antitumor [Figure 2 ] chemokines across diverse solid tumors [Supplementary Figure 2, http://links.lww.com/CM9/C797 ]. No chemokine showed a consistent expression pattern across all tumor types, reflecting cancer heterogeneity, tissue-specific context, and chemokine diversity. However, distinct chemokine signatures within individual tumors may offer insight into the TME and inform the development of chemokine-based immunotherapies. Understanding these context-dependent roles is critical for advancing tumor-specific therapeutic strategies. Figure 1. Open in a new tab Alterations in the expression of pro-tumorigenic chemokines across different solid tumors. Green: Upregulated in tumors (dark green: >20-fold upregulation vs. normal). Gray: Downregulated in tumors (dark gray: >20-fold downregulation vs. normal). Table values are P values (significance of changes), comparison between two groups was performed using unpaired two‑tailed Student’s t ‑test. A P -value < 0.05 was considered statistically significant. ACC: Adrenocortical carcinoma; BLCA: Bladder urothelial carcinoma; BRCA: Breast invasive carcinoma; CCL: Cysteine–Cysteine motif chemokine ligand; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; COADREAD: Colon adenocarcinoma/Rectum adenocarcinoma esophageal carcinoma; CXCL: Cysteine–X–Cysteine motif chemokine ligand; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; GBMLGG: Glioma; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIPAN: Pan-kidney cohort (KICH+KIRC+KIRP); KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LGG: Brain lower grade glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; ns: Not significant; OVCS: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; STES: Stomach and esophageal carcinoma; TGCT: Testicular germ cell tumors; THCA: Thyroid carcinoma; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma; WT: Wilms tumor. Figure 2. Open in a new tab Alterations in the expression of anti-tumor chemokines across various solid tumors. Green: Upregulated in tumors (dark green: >20-fold upregulation vs. normal). Gray: Downregulated in tumors (dark gray: >20-fold downregulation vs. normal). Table values are P values (significance of changes). ACC: Adrenocortical carcinoma; BLCA: Bladder urothelial carcinoma; BRCA: Breast invasive carcinoma; CCL: Cysteine–Cysteine motif chemokine ligand; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL: Cholangiocarcinoma; COAD: Colon adenocarcinoma; COADREAD: Colon adenocarcinoma/Rectum adenocarcinoma esophageal carcinoma; CXCL: Cysteine–X–Cysteine motif chemokine ligand; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; GBMLGG: Glioma; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIPAN: Pan-kidney cohort (KICH+KIRC+KIRP); KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LGG: Brain lower grade glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; ns: Not significant; OVCS: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; STES: Stomach and esophageal carcinoma; TGCT: Testicular germ cell tumors; THCA: Thyroid carcinoma; UCEC: Uterine corpus endometrial carcinoma; UCS: Uterine carcinosarcoma; WT: Wilms tumor; XCL: X–Cysteine motif chemokine ligand. Chemokine expression within the TME is shaped not only by tissue-specific factors but also by genetic mutations, signaling pathway activity, and epigenetic reprogramming. These mechanisms regulate chemokine levels, influencing tumor progression and immune responses. Gain- or loss-of-function mutations in key genes can activate or suppress signaling cascades, thereby altering chemokine expression in cancer cells. [ 27 ] For instance, CXCL9 and CXCL10 are epigenetically silenced through enhancer of zeste homolog 2 ( EZH2 )-mediated lysine 27 on histone H3 (H3K27) trimethylation and DNMT1 -dependent DNA methylation. [ 28 ] Beyond these regulatory layers, tumors may impair chemokine-mediated immune surveillance via genomic deletions—such as CXCL13 loss in colorectal cancer (CRC) [ 29 ] or through oncogene-driven repression, exemplified by the MYC -FMRP- CCL7 axis. [ 30 ] These mechanisms underscore the complexity of chemokine regulation in cancer. By disrupting chemokine signaling, tumors evade immune detection, reduce immune cell infiltration, and establish a microenvironment conducive to growth and metastasis. Deciphering these regulatory networks is critical for designing therapies that restore effective chemokine-mediated immune function. Our analysis reveals pronounced heterogeneity in chemokine expression across tumor types. Given their context-dependent roles, either promoting or inhibiting tumor progression, systematic chemokine profiling is essential to understand their functional impact. Targeting tumor-specific chemokine pathways may enable precision immunotherapies tailored to individual cancer types. Targeting Chemokine Pathways in Cancer Therapy The TME is shaped by spatially regulated chemokine production from tumor cells, immune cells, and stromal elements. [ 31 ] Beyond influencing tumor cell stemness, survival, and invasiveness, chemokines are key regulators of angiogenesis, fibrogenesis, and immune cell recruitment. The selective trafficking of immune cell subsets, driven by differential chemokine receptor expression, plays a central role in orchestrating immune responses within the TME [Figure 3 ]. Although immune tolerance serves protective physiological functions, its tumor-induced form enables immune evasion and is linked to poor clinical outcomes. [ 32 , 33 , 34 ] Targeting chemokine–receptor interactions represents a promising therapeutic strategy to overcome this tolerance by enhancing effector immune cell infiltration or inhibiting recruitment of immunosuppressive populations. The expression and activity of the chemokine axis also serves as a prognostic biomarker for immunotherapy responsiveness and reveals mechanisms of immune escape [Figure 3 ]. Several therapeutic agents including small-molecule inhibitors, neutralizing antibodies, and receptor antagonists are currently under clinical investigation [Supplementary Tables 2 and 3, http://links.lww.com/CM9/C797 ]. The following section highlights major therapeutic approaches targeting chemokine pathways in cancer immunotherapy. Figure 3. Open in a new tab Chemokine-mediated immune cell infiltration in solid tumors. This illustration depicts the key chemokine–chemokine receptor axes that regulate immune cell trafficking into the solid TME. The left panel highlights chemokine pathways that promote anti-tumor immunity by recruiting immune effector cells such as cytotoxic T lymphocytes, helper T cells, NK cells, and APCs to the tumor site. The right panel shows chemokine signals that drive protumor responses by attracting immunosuppressive populations, including Tregs and MDSCs, which facilitate immune evasion and tumor progression. APCs: Antigen-presenting cells; CCL: Cysteine–Cysteine motif chemokine ligand; CCR: Cysteine–Cysteine motif chemokine receptor; CX3CL: Cysteine–X3–Cysteine motif chemokine ligand; CX3CR: Cysteine–X3–Cysteine motif chemokine receptor; CXCL: C-X-C motif chemokine ligand; CXCR: Cysteine–X–Cysteine motif chemokine receptor; DCs: Dendritic cells; G-MDSCs: Granulocytic myeloid-derived suppressor cells; NK: Natural killer cells; M-MDSCs: Monocytic myeloid-derived suppressor cells; MDSCs: Myeloid-derived suppressor cells; TAMs: Tumor-associated macrophages; TME: Tumor microenvironment; Tregs: Regulatory T cells; XCL: X–Cysteine motif chemokine ligand; XCR: X–Cysteine motif chemokine receptor. Inhibition of immunosuppressive chemokine signaling: Strategies and clinical outcomes Differential chemokine receptor expression among immune cell subsets enables the selective recruitment of specific populations, shaping localized inflammation and modulating immune responses with context-dependent pro- or antitumor effects [Figure 4 ]. The following section highlights key chemokine-receptor axes that drive tumor-associated immune tolerance and immunosuppression [Table 1 ], and summarizes the clinical efficacy of small-molecule inhibitors, neutralizing antibodies, and receptor antagonists targeting these pathways. Figure 4. Open in a new tab Chemokine-based strategies in cancer immunotherapy. This diagram illustrates therapeutic approaches leveraging the chemokine system to modulate immune responses in cancer. (A) Highlights strategies that enhance antitumor immunity by increasing the presence or activity of chemokines and their receptors to promote immune cell recruitment within the TME. Key approaches include: (1) Chemokine-secreting oncolytic viruses: Engineered that selectively infect and lyse tumor cells while secreting chemokines to attract immune effector cells. (2) Chemokine–anchoring protein fusions: Chemokines fused to tumor-targeting moieties or ECM-binding domains, anchoring them within the TME to form stable chemotactic gradients and prevent degradation. (3) Immune cells expressing chemokines or receptors: CAR-T, CAR-NK, and CAR-M engineered to express chemokines or homing receptors. These cells enhance tumor infiltration and stimulate recruitment of endogenous immune populations (e.g., cytotoxic T cells and DCs, amplifying antitumor responses and overcoming TME-associated immunosuppression. (B) Depicts strategies to inhibit protumor chemokine signaling, which tumors use to facilitate immune evasion and progression. These interventions use neutralizing antibodies or small-molecule inhibitors targeting tumor-promoting chemokines or their receptors. Ab: Antibody; CAR-M: Chimeric antigen receptor macrophage; CAR-NK: Chimeric antigen receptor natural killer cells; CAR-T: Chimeric antigen receptor T cells; CXCL: Cysteine–X–Cysteine motif chemokine ligand; DCs: Dendritic cells; ECM: Extracellular matrix; mAb: Monoclonal antibody; TME: Tumor microenvironment. Table 1. The major chemokine–chemokine receptor axis in TME promotes immunosuppression. Chemokine Major producing cells High expression in tumors Receptors Receptor-expressing immune cells Function References CXCL12 MSCs, fibroblasts, and at low levels in macrophages and neutrophils Tumor metastasis site, CSC CXCR4 TAMs, Tregs, and MDSCs Driving the recruitment and infiltration of immunosuppressive cells; promoting tumor cell growth, dissemination, and stimulating tumor invasion [ 35 , 41 ] CCL17/CCL22 Tumor cells, CCR7 + cDCs; TAMs EBV + tumors, THCA, LUAD, ACC, PRAD, STAD, ESCC CCR4 Tregs Promoting Tregs recruitment [ 55 , 57 , 58 ] CCL5 Inflammatory cells, cancer cells SKCM, TGCT, KIRC, COAD, breast cancer CCR5 Pro-metastatic TAMs, MDSCs, Tregs Promoting uncontrolled tumor cell proliferation, angiogenesis, apoptosis resistance, invasion, and metastasis; contributing to tumor immunosuppression [ 79 , 80 , 81 , 82 ] CCL2 Tumor cells Breast, lung, hepatocellular, esophageal, prostate, ovarian, and bladder cancers CCR2 MDSCs, Tregs, TAMs, and tumor-promoting monocytes Promoting the initiation, progression, and metastasis of various malignancies; orchestrating an immunosuppressive TME [ 95 , 96 , 102 , 105 , 106 , 107 , 113 ] CXCL8 Macrophages, epithelial cells, and endothelial cells Gastric cancer, breast cancer, prostate cancer, lung cancer, colorectal carcinoma, and melanoma CXCR1/CXCR2 N2 TANs, TAMs, and MDSCs Recruiting N2 TANs, TAMs, and MDSCs, shaping immunosuppressive TME, and promoting the recruitment and proliferation of cancer stem cells, contributing to tumor maintenance, metastasis, and resistance to therapies [ 123 , 124 , 127 , 132 ] CCL20 Activated tumor epithelial cells and myeloid cells HCC, CRC, BRCA, pancreatic cancer, CESC, and RCC CCR6 DCs, ILC3, Th17, Treg, CD8 + T cells, TAMs and B cells Leading to the recruitment of DCs and CCR6 + ILC3s to exert antitumor function; promoting Tregs migration to tumor sites for tumor progression [ 147 , 148 , 149 , 150 ] Open in a new tab ACC: Adrenocortical carcinoma; BRCA: Breast invasive carcinoma; CCL: Cysteine–Cysteine motif chemokine ligand; CCR: Cysteine–Cysteine motif chemokine receptor; cDCs: Conventional dendritic cells; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; COAD: Colon adenocarcinoma; CRC: Colorectal cancer; CSC: Cancer stem cell; CXCL: Cysteine–X–Cysteine motif chemokine ligand; CXCR: Cysteine–X–Cysteine motif chemokine receptor; ESCC: Esophageal squamous cell carcinoma; HCC: Hepatocellular carcinoma; ILC3: Group 3 innate lymphoid cell; KIRC: Kidney renal clear cell carcinoma; LUAD: Lung adenocarcinoma; MDSCs: Myeloid-derived suppressor cells; MSCs: Mesenchymal stem cells; N2: Type II tumor-associated neutrophils; PRAD: Prostate adenocarcinoma; RCC: Renal cell carcinoma; SKCM: Skin cutaneous melanoma; STAD: Stomach adenocarcinoma; TAMs: Tumor-associated macrophages; TANs: Tumor-associated neutrophils; TGCT: Testicular germ cell tumors; Th17: T Helper 17 cell; THCA: Thyroid carcinoma; TME: Tumor microenvironment; Tregs: Regulatory T cells. CXCL12–C–X-C receptor 4 (CXCR4) axis The CXCL12–CXCR4 axis plays a central role in tumor metastasis and immune evasion by recruiting immunosuppressive cells—including TAMs, Tregs, and MDSCs—into the TME. [ 35 ] CXCL12 is primarily produced by mesenchymal stromal cells, fibroblasts, and select immune cells, while CXCR4 is essential for lymphocyte homing and lymphoid organ development. [ 36 , 37 ] In the TME, CXCL12-expressing perivascular fibroblasts guide TGF-β-induced CXCR4 + TAMs to blood vessels, where they differentiate into prometastatic macrophages, promoting vascular permeability and tumor cell intravasation. [ 38 ] In pancreatic ductal adenocarcinoma, Fibroblast activation protein‑positive (FAP + ) cancer‑associated fibroblast (CAF)-derived CXCL12 forms a chemokine barrier that excludes T cells and enforces immunosuppression. [ 39 ] Collectively, this axis supports an immune-excluded TME by enhancing angiogenesis, stromal remodeling, and lymphocyte exclusion. CXCL12 also regulates T-cell trafficking through tumor-associated lymphatics. Upon antigen recognition, CD8 + T cells adjust CXCR4 expression, affecting their tumor retention. [ 40 ] CXCR4 inhibition improves stem-like CD8 + T cell persistence, enhances checkpoint blockade efficacy, and sensitizes tumors to radiotherapy and chemotherapy. [ 41 ] Several CXCR4 antagonists have shown therapeutic potential. Plerixafor (AMD3100, Sanofi) disrupts stromal barriers, increases T-cell infiltration, and synergizes with PD-L1 blockade to suppress tumor growth. [ 42 , 43 , 44 ] It also induces immune activation in colorectal and pancreatic cancers, whereas balixafortide has shown efficacy in metastatic breast cancer. [ 45 , 46 ] The cyclic peptide LY2510924 (Eli Lilly and Company), which selectively blocks stromal-derived factor 1 (SDF-1) binding, is under phase II investigation ( NCT01439568 ). [ 47 , 48 , 49 , 50 ] In a phase I trial, it mobilized CD34 + cells, with stable disease (SD) in 20% of patients; combined with durvalumab, SD increased to 44.4%, including one unconfirmed partial response. [ 51 ] BL-8040 (generic name is Motixafortide, BioLineRx Ltd., Israel), when combined with pembrolizumab and chemotherapy, achieved a 32% objective response rate in pancreatic cancer, along with enhanced CD8 + T-cell infiltration and reduced myeloid suppression. [ 52 ] Despite promising outcomes, resistance to CXCR4 inhibition, particularly in metastatic disease, remains a challenge. This may be driven by redundancy within the chemokine network, allowing compensatory pathways to bypass blockade. Future strategies should prioritize rational combination therapies to overcome resistance and maximize therapeutic benefit. CCL17/CCL22–CCR4 axis The CCL17/CCL22–CCR4 axis plays a central role in tumor immune evasion by recruiting Tregs, which comprise up to 90% of CCR4 + T cells in humans. [ 53 , 54 ] CCL17 and CCL22, produced by tumor cells, TAMs, and dendritic cells (DCs), bind CCR4 on Tregs, promoting their accumulation in the TME. [ 55 , 56 , 57 , 58 , 59 ] This axis is particularly active in ovarian cancer ascites and renal cell carcinoma (RCC), where elevated CCR4 + Treg levels correlate with immunosuppression. [ 53 , 60 ] CCR4 blockade disrupts Treg trafficking and enhances antitumor immunity. Preclinical studies demonstrate that CCR4 antagonists reduce Treg infiltration, boost CD8 + T cell responses, and improve vaccine efficacy. [ 61 , 62 ] In RCC models, CCR4 inhibition also alters myeloid cell polarization, reducing immunosuppressive immature myeloid populations. [ 63 ] Interestingly, CCL22 deficiency improves vaccine responses and prolongs survival in tumor-bearing mice but also increases susceptibility to inflammatory disease, underscoring its dual regulatory role. [ 60 , 64 ] These findings suggest that the CCL22–CCR4 axis functions as an immune checkpoint essential for T-cell regulation. Multiple strategies targeting Treg recruitment via the CCL17/CCL22–CCR4 axis, including neutralizing antibodies, small interfering RNAs (siRNAs), and small-molecule antagonists, have shown encouraging preclinical efficacy (e.g., NCT03674567 ). [ 65 ] Given its role in Treg migration, CCR4 inhibition is being actively explored as a therapeutic approach to restore antitumor immunity. [ 66 , 67 ] The anti-CCR4 monoclonal antibody mogamulizumab has demonstrated Treg-depleting effects and clinical activity in solid tumors. [ 68 , 69 , 70 , 71 ] Combination therapies with programmed cell death protein 1 (PD-1) inhibitors (e.g., nivolumab) have shown modest response rates [27% in hepatocellular carcinoma (HCC)], while those with cytotoxic T‑lymphocyte‑associated protein 4 (CTLA-4) inhibitors have yielded limited benefit (5.3% objective response rate). [ 72 , 73 ] However, combining mogamulizumab with utomilumab (a CD137 agonist) produced partial responses and disease stabilization in a subset of patients. [ 74 ] Additionally, FLX475, a novel small-molecule CCR4 antagonist, is currently being evaluated in combination with pembrolizumab. [ 75 ] In summary, CCR4 remains a promising immunotherapeutic target for Treg depletion, modulation of the TME, and enhancement of antitumor immune responses. CCL5–CCR5 axis The CCL5–CCR5 signaling axis plays a key role in tumor progression by promoting cancer cell proliferation, metastasis, and immune evasion. Aberrant expression of CCL5 and CCR5 has been reported in multiple solid tumors and is associated with lymph node metastasis and poor clinical outcomes. [ 76 , 77 , 78 , 79 ] Elevated CCL5 levels correlate with disease progression in breast, ovarian, gastric, and pancreatic cancers. CCR5 is expressed on a variety of cells, including smooth muscle, epithelial, and endothelial cell, and is preferentially enriched on immunosuppressive populations such as Tregs, TAMs, and MDSCs, which are actively recruited into the tumor by CCL5. [ 80 , 81 , 82 , 83 ] The CCL3/4/5–CCR5 axis also facilitates MDSC mobilization from the bone marrow, enhances precursor proliferation, and recruits CCR5 + macrophages, contributing to immunosuppression and tumor relapse. [ 83 , 84 ] Given these functions, this pathway has emerged as a promising immunotherapeutic target, with early studies supporting its anti-inflammatory and antitumor potential. Despite this promise, CCR5 inhibition remains controversial due to its dual immunomodulatory roles. [ 84 , 85 , 86 , 87 ] The CCR5 antagonist maraviroc showed partial responses in metastatic CRC, potentially through TAM reprogramming. Combined with pembrolizumab, it achieved disease stabilization and longer-than-expected overall survival in heavily pretreated patients ( NCT03274804 ). [ 88 , 89 ] The anti-CCR5 antibody leronlimab is currently being tested in triple-negative breast cancer, while dual CCR2/CCR5 inhibitors such as BMS-813160 (Bristol‑Myers Squibb) are under clinical evaluation in various malignancies. [ 90 , 91 ] However, clinical efficacy data from these trials remain unavailable. Notably, CCR5-targeted therapies have shown limited success in breast cancer, possibly due to CCL5-mediated signaling through alternative receptors such as CCR1 and CCR3, which may bypass CCR5 inhibition and sustain tumor-promoting effects. CCL2–CCR2 axis The CCL2–CCR2 axis is a key driver of tumor progression, promoting cancer cell survival, proliferation, invasiveness, and stemness through activation of mitogen-activated protein kinase (MAPK), Sma- and Mad-related protein (SMAD), mesenchymal-epithelial transition (MET), and Notch signaling pathways. [ 92 , 93 , 94 , 95 , 96 ] CCL2, produced by tumor cells, stromal components, and MDSCs, is also detected in tumor microvessels. [ 10 , 97 , 98 , 99 ] Its elevated expression correlates with increased monocyte and MDSC infiltration and is associated with poor clinical outcomes in both murine models and human cancers. [ 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 ] CCR2, expressed on myeloid cells, T helper 1 cell (Th1)/Th2 lymphocytes, and some dendritic cells, plays a context-dependent role in immunity. While CCR2 deficiency or pharmacological blockade reduces infiltration of immunosuppressive monocytes, MDSCs, and TAMs, thereby suppressing tumor growth, [ 108 , 109 , 110 , 111 ] CCR2 also contributes to the recruitment of conventional type 1 dendritic cells and CD8 + T cells, indicating dual and context-specific functions. [ 112 ] Due to its critical role in recruiting pro-tumor myeloid populations, the CCL2–CCR2 axis remains a promising therapeutic target. Preclinical studies demonstrate that its inhibition reduces immune suppression, limits myeloid cell accumulation, and impairs metastasis, suggesting potential to remodel the TME and enhance antitumor immunity. However, its immunomodulatory complexity necessitates further study. In preclinical models, CCL2–CCR2 blockade effectively reduces TAM infiltration and tumor burden. [ 7 , 113 , 114 , 115 , 116 ] Clinically, the CCR2 antagonist PF-04136309 (Pfizer Inc., USA), combined with FOLFIRINOX (a combination regimen of fluorouracil, oxaliplatin, leucovorin, and irinotecan), showed acceptable safety and a 49% objective response rate in advanced pancreatic cancer. [ 117 ] Similarly, CCX872, a second-generation CCR2 inhibitor, improved 18-month survival (29% vs. 18.6%) when added to FOLFIRINOX. [ 118 ] In contrast, agents such as carlumab (anti-CCL2) and plozalizumab (anti-CCR2) failed to show clinical benefit, leading to early trial termination. [ 119 , 120 , 121 ] Although carlumab transiently suppressed serum CCL2 levels, this effect was not sustained. The absence of antidrug antibodies suggests clinical failure may stem from poor drug persistence, inadequate dosing, or limited in vivo efficacy. Furthermore, as CCL2 can recruit both tumor-promoting and antitumor immune cells, its broad inhibition may paradoxically promote tumor progression, possibly contributing to disappointing trial outcomes. To overcome these limitations, ongoing trials are evaluating dual CCR2/CCR5 inhibitors, such as BMS-813160 (Bristol-Myers Squibb Co., USA), in pancreatic and CRCs, with the goal of enhancing therapeutic efficacy. CXCL8–CXCR1/2 axis The CXCL8 (interleukin-8 [IL-8])–CXCR1/2 axis plays a critical role in tumor progression by activating the phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B (PI3K-AKT), MAPK, and phospholipase C (PLC), [ 122 ] thereby promoting cancer cell survival, invasion, metastasis, and angiogenesis within the TME. [ 123 , 124 , 125 ] CXCL8, secreted by macrophages, epithelial, and endothelial cells, primarily targets neutrophils and granulocytic MDSCs through CXCR1 and CXCR2. [ 126 , 127 ] This signaling axis induces the formation of neutrophil extracellular traps by granulocytic MDSCs, facilitating thrombosis and metastatic dissemination. [ 126 , 128 , 129 ] In Ras-driven tumors, [ 130 , 131 , 132 ] CXCL8 also recruits TANs and promotes the expansion of type 2 neutrophils, which suppress cytotoxic immune responses. Neutrophil extracellular traps formed via CXCR1/2 activity encapsulate tumor cells and prevent contact with CD8 + T cells and NK cells, shielding them from immune attack. [ 133 ] Additionally, this axis enhances angiogenesis through neutrophil recruitment, further driving tumor progression. [ 103 , 134 ] Preclinical studies have shown that CXCR1/2 antagonists reduce tumor growth in xenograft models, [ 135 , 136 , 137 ] highlighting the therapeutic potential of targeting the CXCL8–CXCR1/2 axis to overcome immune evasion. Elevated IL-8 levels are associated with immunosuppression and resistance to immune checkpoint inhibitors (ICIs). [ 134 , 138 ] Inhibition of the IL-8–CXCR1/2 pathway enhances ICI efficacy and suppresses tumor growth in preclinical models. [ 139 , 140 , 141 , 142 ] The anti-IL-8 antibody BMS-986253 (Bristol-Myers Squibb Co.) stabilized disease in 73% of patients and improved response to nivolumab in PD-1-resistant melanoma. [ 143 , 144 ] In breast cancer, the CXCR1/2 inhibitor reparixin reduced cancer stem cell populations and achieved a 30% response rate when combined with paclitaxel, underscoring its potential to target tumor-initiating cells. [ 145 , 146 ] Emerging clinical data support reparixin as a promising agent for breast cancer, where it impairs TAN function and stemness-related tumor activity. CCL20–CCR6 axis The CCL20–CCR6 axis, originally associated with inflammatory conditions, has emerged as a key modulator in various cancers, including HCC, CRC, and RCC. [ 147 ] Its dual role in tumor biology stems from the broad expression of CCR6 across diverse immune cell subsets, such as DCs, innate lymphoid cells (ILC3s), T helper 17 cells, Tregs, and TAMs. [ 148 , 149 ] In antitumor contexts, this axis facilitates DC recruitment to the tumor site, enabling antigen capture and migration to lymph nodes for tumor-specific T-cell priming, as observed in breast cancer. [ 150 ] IL-12-activated CCR6 + ILC3s also promote lymphoid infiltration and suppress melanoma growth. [ 151 ] Moreover, cisplatin-induced CCL20 and interleukin-1beta (IL-1β) stimulate ILC3s to produce CXCL10, enhancing CD4 + and CD8 + T-cell infiltration into tumors. [ 152 ] Conversely, the axis also supports immune evasion and tumor progression. Elevated CCR6 expression on circulating Tregs facilitates their migration into CCL20-rich tumors, where CCL20 levels correlate with increased Treg accumulation. In HCC, lipid-laden TAMs secrete CCL20 to recruit CCR6 + Tregs, promoting tumor growth. [ 153 ] In CRC, receptor activator of nuclear factor-kappaB (RANK) overexpression or RANK ligand (RANKL) stimulation upregulates CCL20, enhancing CCR6 + Treg infiltration and driving cancer stemness and malignant progression. [ 154 ] In RCC, CCL20–CCR6 signaling mediates TAM-induced EMT via AKT activation, contributing to poor clinical outcomes. [ 155 ] Collectively, these findings underscore the context-dependent nature of the CCL20–CCR6 axis, which can either promote antitumor immunity or facilitate tumor progression, depending on the dominant immune subsets and tumor microenvironmental cues. Its broad cellular expression poses challenges for therapeutic targeting, necessitating cell-specific strategies to effectively harness its immunomodulatory potential. Enhancing effector immune cell recruitment to the TME via chemokines This section highlights key chemokine–chemokine receptor axes that coordinate antitumor immune responses within the TME [Table 2 ]. Table 2. The major chemokine–chemokine receptor axis in TME promotes antitumor immune response. Chemokine Major producing cells High expression in tumors Receptors Receptor-expressing immune cells Function References CXCL9/10/11 Monocytes, macrophages, endothelial cells, cancer cells, and fibroblasts NSCLC, BRCA, OV CXCR3 Monocytes, NK cells, NKT cells, DCs, Th1, and CTLs Regulating antitumor immune cell migration, activation, and differentiation [ 19 , 156 , 157 , 158 , 159 ] XCL1 T, NK, and NKT cells CRC, SKCM, BRCA, HNSC, LUAD XCR1 cDCs Recruiting cDCs, stabling T cell–DC interactions, and thereby increasing the pool of antigen-specific CD8 + T cell function [ 171 , 172 ] TM–CXCL16 Mostly on myeloid cells, but also on fibroblasts, endothelial cells, and cancer cells KIPAN, CRC, OV, BRCA, HNSC CXCR6 CD8 + T cells, effector CTLs, and NKT cells Promoting CTLs recruitment and retention within TME [ 178 , 179 , 180 , 181 , 182 , 184 ] CX3CL1 Expressed on epithelial cells, endothelial cells, smooth muscle cells, neurons, and DCs OVCS and gastric, pancreatic and lung cancer, CRC CX3CR1 Tissue-resident macrophages, monocytes, CD8 + T cells, DCs, NK Enhancing the tumor-infiltrating lymphocytes (TILs) including CTLs and NK cells, and promoting their anti-tumor activity [ 190 , 191 , 192 ] Open in a new tab BRCA: Breast invasive carcinoma; CRC: Colorectal cancer; cDCs: Conventional dendritic cells; CTLs: Cytotoxic T lymphocytes; CX3CL: Cysteine–X3–Cysteine motif chemokine ligand; CX3CR: Cysteine–X3–Cysteine motif chemokine receptor; CXCL: Cysteine–X–Cysteine motif chemokine ligand; CXCR: Cysteine–X–Cysteine motif chemokine receptor; DCs: Dendritic cells; HNSC: Head and neck squamous cell carcinoma; KICH: Kidney chromophobe; KIPAN: Pan-kidney cohort (KICH+KIRC+KIRP); KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LUAD: Lung adenocarcinoma; NK: Natural killer; NSCLC: Non-small cell lung cancer; OVCS: Ovarian serous cystadenocarcinoma; SKCM: Skin cutaneous melanoma; Th1: T helper 1 cell; TILs: Tumor infiltrating lymphocytes; TM–CXCL16: Transmembrane Cysteine–X–Cysteine motif chemokine ligand 16; TME: Tumor microenvironment; XCL: X-C motif chemokine ligand; XCR: X–Cysteine motif chemokine receptor. CXCL9/10/11–CXCR3 axis CXCL9, CXCL10, and CXCL11 are ELR (Glu-Leu-Arg)-negative CXC chemokines with well-established antiangiogenic and tumor-suppressive properties. [ 156 , 157 , 158 , 159 ] These chemokines are primarily produced by monocytes, macrophages, endothelial cells, cancer cells, and fibroblasts in response to interferon-gamma (IFN-γ) and TNF-α. All three selectively bind the chemokine receptor CXCR3. [ 19 ] CXCR3 is expressed on multiple immune subsets, including T cells, NK cells, natural killer T cells, monocytes, DCs, and CTLs. Although naïve T cells express low levels of CXCR3, its expression is rapidly upregulated upon activation by antigen-presenting cells (APCs), facilitating Th1 polarization. [ 160 ] This chemokine-receptor axis plays a pivotal role in immune cell trafficking, activation, and differentiation. In particular, it guides effector T cells and NK cells into tumor sites, a prerequisite for effective immune checkpoint blockade (ICB) targeting PD-1/PD-L1. [ 161 , 162 ] CXCR3 also mediates distinct downstream signaling pathways depending on the ligand. CXCL9 and CXCL10 signal through the receptor’s C-terminal domain, activating transcription factors T-bet and retinoic orphan receptor gamma t (RORγt) via signal transducer and activator of transcription 1 (STAT1), STAT4, and STAT5 pathways. This promotes the differentiation of naïve T cells into type 1 regulatory Foxp3 − T cells or T Helper 17 cells. In contrast, CXCL11 interacts with the receptor’s intracellular loop, suppresses RORγt expression, and induces the polarization of type 1 regulatory or Th2 cells via the p70S6 kinase/mTOR pathway. [ 163 , 164 , 165 ] In vivo studies have shown that tumor cells overexpressing CXCL10 exhibit significantly reduced growth, associated with suppressed angiogenesis and mitotic activity. [ 166 , 167 ] Therapeutic strategies including ICB, recombinant oncolytic viruses (OVs), and cytokine therapies can enhance intratumoral CXCL9/10/11 levels and CXCR3 expression, thereby promoting T-cell infiltration and tumor suppression. [ 166 , 167 , 168 , 169 ] Interestingly, CXCR3 is not required for CD8 + T cell entry into tumors but is essential for enhancing their effector functions during PD-1 blockade. [ 161 ] These findings support the axis as a key modulator of anti-PD-1 immunotherapy efficacy in preclinical models. Moreover, recent evidence shows that co-expression of CCL5 and CXCL9 is a hallmark of immunoreactive tumors with high CTL infiltration. [ 125 ] The coordinated activity of tumor-derived CCL5 and myeloid cell-derived, IFN-γ-inducible CXCR3 ligands facilitates effective T cell-mediated tumor rejection. [ 125 ] Altogether, targeting and enhancing the CXCL9/10/11–CXCR3 axis in the TME represents a promising strategy to boost effector immune cell recruitment and amplify antitumor immunity. XCL1–XCR1 axis XCL1 is primarily secreted by stem-like CD8 + T cells, NK cells, and Th1 cells. Its exclusive receptor, XCR1, a rare chemokine receptor, is selectively expressed on conventional dendritic cells (cDCs). [ 170 , 171 , 172 ] Notably, XCR1 expression is confined to the CD8 + cDCs subset, where it functions as a potent and highly specific chemoattractant. [ 173 , 174 ] During sustained interactions with antigen-presenting DCs, CD8 + T cells release XCL1, thereby promoting the recruitment and expansion of antigen-specific CTLs. [ 175 ] Although cDCs are currently the only cells known to express XCR1, XCL1 is also produced by other immune populations, such as invariant natural killer T (iNKT) cells. iNKT cell-driven XCL1–XCR1 signaling has been shown to exacerbate airway hyperresponsiveness in allergic asthma by recruiting CD103 + DCs to the lung. [ 176 ] Overall, the XCL1–XCR1 axis is a key regulator of cytotoxic immunity, particularly in antitumor responses. CXCL16–CXCR6 axis The CXCL16/CXCR6 axis plays a dual, context-dependent role in the TME. CXCL16 is expressed by myeloid cells, fibroblasts, endothelial cells, and tumor cells, whereas its receptor, CXCR6, is found on activated T cells, NK cells, natural killer T cells, and plasma cells. [ 177 , 178 , 179 , 180 , 181 ] Frequently upregulated in tumors, this axis exerts opposing effects depending on the form of CXCL16. The transmembrane form (TM–CXCL16) inhibits tumor growth and recruits lymphocytes, aligning with improved prognosis. It also functions as an adhesion molecule and scavenger receptor on immune cells, enhancing antitumor immunity through iNKT cell activation and the maintenance of tissue-resident memory T cells. [ 182 , 183 , 184 , 185 ] Conversely, the soluble form (S–CXCL16) promotes tumor progression and angiogenesis, partly by activating the PI3K/AKT pathway via CXCR6, and is linked to poor clinical outcomes. [ 182 , 183 , 186 , 187 , 188 , 189 ] Although the CXCL16/CXCR6 axis holds promise for immunotherapy, the distinct signaling mechanisms of TM–CXCL16 and the basis of its opposing roles remain unclear and require further elucidation. CX3CL1–CX3CR1 CX3CL1 is a transmembrane chemokine that can be proteolytically cleaved into a soluble form, similar to CXCL16. [ 190 ] These two forms have distinct but complementary functions mediated through the receptor CX3CR1. The membrane-bound form (TM–CX3CL1), expressed by activated epithelial cells, DCs, and neurons in the brain and spinal cord, functions as an adhesion molecule by binding to CX3CR1 on infiltrating immune cells, including NK cells, CD8 + T cells, monocytes, and tissue-resident cells such as microglia and DCs. [ 191 , 192 ] The CX3CL1–CX3CR1 axis plays an important antitumor role by facilitating immune cell infiltration. High CX3CL1 expression is associated with increased tumor-infiltrating lymphocytes, including CTLs, intratumoral DCs, and NK cells, and correlates with a favorable prognosis in colorectal and breast cancers. [ 193 , 194 ] Similarly, elevated CX3CL1 levels are linked to prolonged survival in LUAD patients. [ 195 ] These findings suggest that CX3CL1 enhances antitumor immunity by promoting the recruitment of CD8 + T cells, NK cells, DCs, and macrophages. However, CX3CL1–CX3CR1 signaling can also promote tumor progression in certain cancers, driving tumor cell proliferation, migration, invasion, adhesion, resistance to apoptosis, and metastatic spread—particularly in pancreatic, colorectal, and prostate cancers. [ 190 ] In lung cancer models, CX3CR1-deficient mice exhibit smaller, less vascularized primary tumors, reduced macrophage infiltration, and fewer metastases compared to wild-type counterparts. [ 196 ] Taken together, while the CX3CL1–CX3CR1 axis supports antitumor immunity, its context-dependent pro-tumor functions highlight the need for deeper mechanistic insights before it can be effectively leveraged for cancer therapy. Targeting chemokine–receptor signaling presents a compelling strategy to modulate the tumor immune microenvironment. Although some agents, particularly in combination with chemotherapy or immunotherapy have shown clinical promise, others, such as the CCL2 inhibitor carlumab, have demonstrated limited efficacy due to pathway redundancy and suboptimal pharmacokinetics. Several factors influence the therapeutic effectiveness of chemokine-targeted small molecules: (1) Redundant signaling: Inhibiting a single chemokine may trigger compensatory upregulation of others, diminishing therapeutic impact. (2) Dual immune functions: Many chemokines exert both pro- and antitumor effects by recruiting diverse immune subsets. For example, CXCL10 attracts CTLs and NK cells, but also facilitates Treg infiltration. A clear understanding of chemokine function within specific tumor contexts is therefore essential to avoid counterproductive immune modulation. (3) Off-target toxicity: Receptors such as CXCR4 are broadly expressed in healthy tissues, including hematopoietic stem cells. Their inhibition can result in adverse effects like bone marrow suppression and hepatotoxicity. (4) Delivery and stability: As small, rapidly degraded proteins, chemokines require improved delivery platforms, such as sustained-release formulations or gene therapies to ensure therapeutic stability and efficacy. (5) Clinical trial design: Many studies lack appropriate patient stratification based on chemokine expression or TME features. Inadequate dosing and scheduling further limit outcomes. (6) Preclinical limitations: Conventional mouse models do not fully capture the complexity of human chemokine networks, often overestimating efficacy in translational studies. To address these challenges, future strategies should focus on biomarker-guided patient selection and rational combination therapies. Promising avenues include combining chemokine inhibitors with ICB (e.g., PD-1/CTLA-4), chemotherapy, or radiotherapy. Additionally, the development of bispecific or multitarget agents, such as dual CCR2/CCR5 antagonists, may further enhance clinical efficacy in cancer treatment. Chemokine-Mediated Formation of TLSs in Tumors TLSs are ectopic lymphoid aggregates that form in nonlymphoid tissues during chronic inflammation, including within tumors, where they mediate context-dependent immune responses. [ 197 ] Typically located at tumor margins, TLSs facilitate localized immune activation and reflect lymphoid neogenesis driven by sustained chemokine and cytokine signaling. [ 198 , 199 , 200 , 201 , 202 , 203 ] They support the proliferation and activation of T and B cells, contributing to long-term antitumor immunity. TLS development is regulated by a network of lymphoid chemokines and cytokines, including CCL19, CCL21, CXCL13, CCL17, and CCL22, which coordinate immune cell recruitment and spatial organization within inflamed tissues. [ 204 , 205 ] The CXCL13–CXCR5 axis guides B-cell migration and follicular formation, whereas the CCL19/CCL21–CCR7 pathway directs T cells and DCs into TLSs. Lymphotoxins α and β, via lymphotoxins β receptor signaling, further stimulate stromal activation and lymphoid tissue architecture. [ 206 ] Of note, CCL21 produced by lymphatic vessels to facilitate lymphocyte migration to draining lymph nodes, has also been detected adjacent to TLSs, underscoring mechanistic parallels between secondary and tertiary lymphoid organogenesis. [ 204 , 207 ] Pan-cancer analyses have identified key TLS-inducing chemokines, such as CCL19, CCL21, CXCL12, and CXCL13, as well as a broader 12-chemokine signature (CCL2, CCL3, CCL4, CCL5, CCL8, CCL18, CCL19, CCL21, CXCL9, CXCL10, CXCL11, and CXCL13) associated with TLS presence across diverse tumor types. [ 197 , 208 , 209 , 210 , 211 , 212 , 213 , 214 ] This signature reflects significant inter- and intra-tumoral heterogeneity in TLS abundance and is particularly enriched in LUAD and lung squamous cell carcinoma. [ 215 ] While strongly linked to TLS formation, the individual contributions and clinical relevance of these chemokines remain to be fully clarified. Data from TCGA and immunotherapy cohorts suggest that the 12-chemokine signature may serve as a pan-cancer biomarker for predicting response to ICB. [ 211 , 216 ] Its expression correlates with indicators of heightened tumor immunogenicity, including increased tumor mutational burden, immune cell infiltration, and cytolytic activity, and is associated with an inflamed, immune-active TME. Despite its potential, clinical implementation of the 12-chemokine signature is hindered by the lack of standardized diagnostic assays. Current evaluations rely on research-grade platforms, and further validation is needed to refine chemokine subsets for disease-specific applications. Additionally, the cellular sources of these chemokines may vary across TLS maturation stages. For example, in high-grade serous ovarian carcinoma, CXCL13 is initially produced by CD4 + T cells in early TLSs but later shifts to CD21 + follicular DCs in mature structures. [ 217 ] In contrast to TLS-enriched tumors, certain cancers, especially those in immunologically privileged sites, exhibit low expression of TLS-associated chemokines such as CXCL12, CXCL13, and CCL21, resulting in sparse or absent TLSs. [ 218 , 219 ] For example, pancreatic ductal adenocarcinoma shows diminished chemokine signatures and reduced TLS density, likely due to suppression by its dense fibrotic stroma. [ 220 ] TLS formation is initiated by chemokines and cytokines released from leukocytes and stromal cells. These signals upregulate lymphotoxin-α1β2 on lymphocytes and recruit them via high endothelial venules, promoting their spatial organization into discrete T and B cell zones, thereby driving TLS maturation. [ 221 , 222 , 223 ] Growing interest in TLSs stems from their potential to enhance antitumor immunity and improve responses to therapies such as ICB. [ 224 , 225 ] Although recent studies implicate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in TLS initiation via endothelial-T cell cross talk, [ 226 ] chemokines and cytokines remain central to TLS induction. A key determinant of TLS presence is tumor permissiveness, which varies by cancer type and microenvironmental context. The functional impact of TLSs is shaped by the TME [Supplementary Table 4, http://links.lww.com/CM9/C797 ]. In non-fibrotic, immune-inflamed (“hot”) TMEs, TLSs are thought to support T-cell effector function, enhance antigen presentation, and increase responsiveness to immunotherapy. In contrast, fibrotic TMEs characterized as immune-excluded or “cold” impede TLS development through ECM deposition that blocks immune cell infiltration and disrupts TLS architecture. Fibroblast-derived cytokines, such as TGF-β and IL-6, may further promote immunosuppressive phenotypes by fostering regulatory B cells or exhausted T cells. In some cases, TLSs in fibrotic tumors may sustain chronic inflammation and paradoxically facilitate tumor progression. [ 227 ] Variability in TLS maturation and spatial positioning likely contributes to their divergent prognostic significance across cancer types. In HCC, peritumoral TLSs are linked to higher recurrence rates and poorer outcomes, whereas intratumoral TLSs correlate with improved prognosis. [ 228 ] In cutaneous melanoma metastases, TLS prognostic value is influenced by cellular composition: TLSs with fewer CD21 + B cells are associated with better outcomes, whereas low activation-induced cytidine deaminase positive (AID + ) B cell content predicts poorer prognosis. [ 229 ] Similarly, in HCC and CRC, TLSs exhibiting primary or secondary follicle-like structures are linked to reduced recurrence risk compared to unstructured lymphoid aggregates. [ 228 , 230 ] Current definitions of peritumoral TLSs often fail to distinguish between stromal-localized TLSs and those at the invasive tumor margin. These spatial and compositional differences may significantly influence their prognostic relevance. Elucidating the chemokine-driven mechanisms that govern TLS formation and function could inform therapeutic strategies aimed at enhancing TLS induction, ultimately improving the efficacy of cancer immunotherapy. Strategies for Localized Chemokine Delivery in the TME To boost antitumor immunity, researchers have explored localized overexpression of chemokines that selectively recruit effector immune cells. Delivery strategies include OVs and chemokine–antibody fragment conjugates [Table 3 and Figure 4 ]. Table 3. Strategies for increasing chemokine expression in TME to recruit effector antitumor immune cells. Chemokines Methods Applications Models Mechanisms References CXCL10 Expression by oncolytic virus Combining with anti-PD-1 antibody A mouse colon cancer model Increasing the cell number of CXCR3 + T cells in TME [ 236 ] CXCL9 Encoding CXCL9 by oncolytic vesicular stomatitis virus Adoptive cell therapy Murine syngeneic plasmacytoma (5TGM1) and NSCLC (LM2) tumor models; human FaDu-Luc tumor xenografts Mediating the recruitment of activated CD8 + cytotoxic T cells and CD4 + T cells [ 241 ] CXCL11 Armed oncolytic vaccinia virus with CXCL11 Combining with cancer vaccines Murine AB12 mesothelioma model Enhancing local numbers of CD8 + CTLs and levels of granzyme B, while reducing expression of several suppressive molecules, TGF-β, COX2, and CCL22 in the TME; Increasing CD8 + T cells function in spleen and other lymph organs [ 242 ] CCL5 Oncolytic virus expressing a secretable scFv of EGFR linked to CCL5 by an Fc knob-into-hole strategy Targeted therapy for tumors EGFR + glioblastoma (GBM) mouse model Enhancing the migration and activation of NK cells, macrophages, and T cells [ 233 ] CXCL10 Linked to the single-chain variable fragment of the EGFR antibody Combining with glioma lysate-pulsed DCs-activated CTLs A mouse model of glioma Increasing the number of brain-infiltrating lymphocytes and the frequency of CXCR3 + CD8 + T cells; enhancing glioma-specific IFN-γ responses and cytotoxicity [ 245 ] CCL10 Antibody-chemokine fusion protein containing the anti-human Endoglin antibody in the single-chain variable fragment format and human CXCL10 Combining with adoptive cytokine-induced killer (CIK) cell immunotherapy Human hepatocellular carcinoma-bearing nude mice Increasing the tumor-infiltrating cytokine-induced killer cells, serum levels of IFN-γ, and tumor cell apoptosis, accompanied with decreased tumor proliferation and angiogenesis [ 246 ] CCL4 Generating a fusion protein containing CCL4 and the collagen-binding domain (CBD) of von Willebrand factor Combining with checkpoint inhibitor (CPI) immunotherapy B16F10 melanomas and EMT6 breast tumors mouse models Promoting recruitment of CD103 + DCs and CD8 + T cells and improving the antitumor effect of CPI immunotherapy [ 247 ] Open in a new tab CCL: Cysteine–Cysteine motif chemokine ligand; CIK: cytokine-induced killer; COX2: Cyclooxygenase-2; CPI: Checkpoint inhibitor; CTLs: Cytotoxic T lymphocytes; CXCL: Cysteine–X–Cysteine motif chemokine ligand; CXCR: Cysteine–X–Cysteine motif chemokine receptor; DCs: Dendritic cells; EGFR: Epidermal growth factor receptor; GBM: glioblastoma; IFN-γ: Interferon-gamma; NSCLC: Non-small cell lung cancer; PD-1: Programmed cell death protein 1; scFv: Single‑chain variable fragment; TGF-β: Transforming growth factor-beta; TME: Tumor microenvironment. OVs-mediated chemokine delivery “Hot” tumors, characterized by robust lymphocyte infiltration into the TME, respond more effectively to immunotherapy than “cold” tumors, which lack substantial immune cell presence. [ 231 , 232 , 233 ] Enhancing chemokine gradients within the TME offers a promising strategy to convert cold tumors into hot ones by promoting effector immune cell recruitment. However, the rapid degradation of chemokines in vivo limits their utility as standalone therapeutics. To overcome this, strategies that ensure sustained chemokine expression in the TME are needed. Oncolytic virotherapy has emerged as a promising approach in this context. [ 234 , 235 , 236 ] OVs, engineered to replicate selectively in tumor cells, induce tumor cell lysis and stimulate immune responses. Tumor lysis releases tumor-associated antigens, activates APCs, and initiates both innate and adaptive immunity via pathogen- and damage-associated molecular pattern signaling. Furthermore, OVs serve as effective vectors for delivering immunostimulatory genes, including chemokines. [ 237 , 238 , 239 ] Preclinical studies have shown that chemokine-expressing OVs can enhance antitumor immunity. In a murine colon cancer model, an adenovirus encoding CXCL10 (advCXCL10) combined with anti-PD-1 therapy significantly increased CXCR3 + T-cell infiltration and improved response to ICB. [ 240 ] In multiple tumor models, vesicular stomatitis virus (VSV)–CXCL9 elevated intratumoral CXCL9 levels and markedly enhanced CD8 + and CD4 + T cell recruitment compared with control virus. [ 241 ] Similarly, a tumor-selective vaccinia virus expressing CXCL11 promoted robust infiltration of tumor-specific T cells in a mesothelioma model and induced systemic antitumor immunity, supporting its potential to enhance both local and systemic therapeutic responses. [ 242 ] An oncolytic adenovirus (Ad5F11bSP-Rantes), engineered to express the CCL5 (RANTES) gene within the E3 region, exhibited both tumor-lytic activity and immune cell recruitment, resulting in synergistic antitumor effects in a triple-negative breast cancer xenograft model. [ 243 ] Another approach utilized a T4 fibritin–CXCL12 fusion protein inserted into the adenoviral fiber tail to selectively infect and lyse CXCR4 + /CXCR7 + breast cancer cells. In glioblastoma, an oncolytic herpes simplex virus type 1 was designed to express a secretable single-chain variable fragment (scFv) of the epidermal growth factor receptor (EGFR)-targeting antibody cetuximab fused to CCL5 using an Fc knob-into-hole strategy (OV-Cmab-CCL5). This construct enabled sustained intratumoral CCL5 expression and selective targeting of EGFR + tumor cells. [ 233 ] OV-Cmab-CCL5 significantly increased NK cell, macrophage, and T-cell infiltration, inhibited tumor growth, and extended survival in glioblastoma-bearing mice. OVs offer several advantages for cancer therapy, including tumor specificity, genetic tractability, scalable manufacturing, and demonstrated clinical safety. [ 244 ] Although capable of systemic delivery and selective tumor targeting while sparing normal tissues, current virotherapies remain insufficient for advanced-stage cancers. Continued innovation is necessary to overcome these limitations and improve therapeutic outcomes in late-stage disease. Antibody-conjugated chemokine delivery An alternative strategy to enhance chemokine levels within the TME involves fusing chemokines to antibody fragments that selectively bind tumor-associated surface antigens. Several bispecific antibodies and chemokine–antibody fusion proteins are currently in clinical development or have been approved for cancer treatment. [ 236 ] One example is IP10-EGFRvIIIscFv, a recombinant fusion protein linking mouse CXCL10 (IP-10) to a scFv targeting EGFRvIII. This construct retains both EGFRvIII-binding specificity and CXCL10-mediated chemotactic activity. [ 245 ] In glioma models, IP10-EGFRvIIIscFv synergized with CD8 + T cells to inhibit tumor growth and prolong survival by enhancing infiltration of CXCR3 + CD8 + lymphocytes into the brain. [ 245 ] Another construct, hENGscFv/hIP-10, combines a human anti-endoglin scFv with CXCL10. In a HCC model, this fusion protein improved the efficacy of cytokine-induced killer cell therapy, increasing intratumoral cytokine-induced killer infiltration, IFN-γ secretion, cytotoxicity, and reducing tumor proliferation and angiogenesis. [ 246 ] Reduced CCL4 expression in the TME has been associated with the absence of CD103 + DCs, which are essential for effective checkpoint blockade responses. To overcome this, a fusion protein was engineered by linking CCL4 to the collagen-binding domain of von Willebrand factor, enabling localized delivery and recruitment of CD103 + DCs and CD8 + T cells. This approach enhanced the efficacy of ICIs across multiple tumor models, including those otherwise resistant to therapy. [ 247 ] Collectively, chemokine–antibody fusion proteins represent a promising strategy to potentiate immunotherapy by improving immune cell trafficking and enhancing the therapeutic impact of adoptive cell transfer and checkpoint blockade. Integrating Chemokine Axis Targeting with Other Immunotherapies Chemokine receptor inhibitors have demonstrated limited effectiveness as monotherapies in solid tumors, and their combination with ICIs has produced only modest benefits. Current research is investigating their use alongside next-generation immunotherapies [Table 4 ]. Table 4. Strategies of targeting chemokine–chemokine receptor axis to enhance anti-tumor immunotherapy efficacy. Chemokine or chemokine receptors Methods Combined immunotherapy Models Mechanisms References CCL3 and CCL20 Injecting with CCL3 and CCL20 via the tail vein directly DC-based vaccines A mouse gastric tumor and metastases model Enhancing T cell-specific killing activity [ 250 ] CXCL10 Intratumoral injection of a plasmid coding CXCL10 DCs pulsed with glioma cell lysate subcutaneously A mouse prostate cancer model Attract T cells more efficiently and enhancing CTL activity [ 251 ] CCL21 Intramuscularly with plasmid DNA expressing CCL21 and tumor-specific antigen DNA-based vaccine A breast cancer mouse model with syngeneic Her2/neu + tumor cells Induction of a TH1-polarized immune response and substantial improvement of the protective effect of the DNA vaccine [ 252 ] CCL5 CCL5 expressed by vaccinia virus Tumor lysates vaccine Mouse tumor model Promoting T cell migration and Th1 response [ 253 ] CXCR2 Introducing CXCR2 into GPC3 CAR-T cells Adoptive GPC3 CAR-T cell therapy A mouse hepatocellular carcinoma tumor model Improving CAR-T cells trafficking and migration ability [ 266 ] CXCR1 Modified CAR-NK cells by electroporating mRNA construct encoding CXCR1 Adoptive NKG2D CAR-NK cell therapy A human head and neck cancer xenograft model was established in NSG mice Enhancing CAR-NK cells trafficking to tumors and increasing anti-tumor response [ 271 ] CXCR5 Cloning CXCR5 coding sequence into the EGFR CAR construct Adoptive EGFR CAR-T cell therapy A human lung cancer xenograft model in NSG mice Improving T cell infiltration to the tumors [ 273 ] CCL19 Cloning IL-7, CCL19 coding sequences into CAR construct Adoptive CAR-T cell therapy Mouse model with patient-derived xenograft of mesothelin-positive pancreatic cancers; a human hepatocellular carcinoma (HCC) and pancreatic carcinoma xenografts mouse model Leading to an increase in not only CAR-T cells but also non-CAR-T cells within the tumor tissues, and generating memory responses against tumors [ 274 , 275 , 276 ] Open in a new tab CAR-NK cells: Chimeric antigen receptor NK cells; CAR-T cells: Chimeric antigen receptor T cells; CCL: Cysteine–Cysteine motif chemokine ligand; CCR: Cysteine–Cysteine motif chemokine receptor; CTL: Cytotoxic T lymphocyte; CXCL: Cysteine–X–Cysteine motif chemokine ligand; CXCR: Cysteine–X–Cysteine motif chemokine receptor; DCs: Dendritic cells; EGFR: Epidermal growth factor receptor; GPC3: Glypican-3; HCC: Hepatocellular carcinoma; HER2: Human epidermal growth factor receptor 2; IL-7: Interleukin-7; NKG2D: Natural killer group 2, member D; NSG: NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ; Th1: T helper 1 cell. Integration of chemokines with cancer vaccines Vaccines are designed to induce protective immunity against pathogens, but those containing weakly immunogenic antigens often require adjuvants to enhance their effectiveness. Chemokines, a family of small chemoattractant proteins that regulate immune cell trafficking and function, have emerged as promising adjuvants due to their ability to modulate lymphocyte development, activation, and effector responses. [ 248 , 249 ] Chemokine-based adjuvants influence both the strength and direction of immune responses elicited by DNA, protein, subunit, or peptide vaccines. However, their clinical application remains limited by challenges such as dose-dependent toxicity, instability, and short in vivo half-lives. These obstacles are being addressed through strategies like liposomal or nanoparticle encapsulation and co-delivery of chemokine expression vectors with DNA or protein-based vaccines. Cancer vaccines have largely failed to generate robust T and B cell responses, often due to poor recruitment and activation of immune effectors. Exploiting chemokine-mediated cell trafficking offers a means to enhance immune cell infiltration into tumors. For instance, DCs recruited by CCL3 and CCL20 and transduced with the tumor-associated antigen melanoma antigen gene 1 (MAGE-1) via adenoviral vectors induced strong gastric cancer-specific responses both in vitro and in vivo . [ 250 ] In another study, glioma-bearing mice treated with glioma cell lysate-pulsed DCs and intratumoral plasmid-encoded CXCL10 showed significantly improved survival, attributed to enhanced recruitment of activated DCs and CXCR3 + T cells. [ 251 ] CCL21, which binds CCR7 on mature DCs and lymphocytes, promotes Th1 polarization and directs T cell trafficking to secondary lymphoid tissues. Its intratumoral administration in HCC models increased T cell infiltration, slowed tumor progression, and prolonged survival. [ 252 ] CCL21 is constitutively expressed in lymphoid tissues, where it binds CCR7 on mature DCs and specific T and B cell subsets. It is essential for guiding DC–T cell interactions and initiating adaptive immune responses. In contrast, CCL5 directs T-cell migration to inflamed or damaged tissues and supports Th1 polarization. In mice, sequential administration of tumor lysate and a CCL5-expressing vaccinia virus markedly suppressed tumor growth and extended survival. [ 253 ] DNA vaccines stimulate antigen-specific cellular and humoral immune responses by encoding foreign antigens; however, their clinical efficacy remains limited due to low immunogenicity and poor translation from animal models to humans. Enhancing these responses through coadministration of chemokine-expressing plasmids or chemokine-based DNA vaccine formulations has shown considerable promise. CXCL10, delivered as a glycosylphosphatidylinositol (GPI)-anchored fusion protein, has been investigated in NK cell-based tumor immunotherapy. A CXCL10–mucin–GPI fusion, which enhances NK cell recruitment, serves as a novel adjuvant strategy in cellular immunotherapy. [ 254 , 255 ] This modular construct comprising a chemokine domain, mucin-like spacer, and GPI anchor, provides a versatile platform for directing immune cell trafficking in various therapeutic contexts. Additionally, CXCL10 and CCL7 fused to lymphoma immunoglobulin variable regions have induced chemotactic responses in vitro and inflammatory activity in vivo . Engineering immune cells with chemokine or receptor expression Chimeric antigen receptor (CAR) immune cell therapy has achieved substantial success in hematologic malignancies and is increasingly recognized as a standard treatment for these cancers. However, its effectiveness in solid tumors remains limited due to several barriers, including inefficient infiltration, poor accumulation, limited persistence of CAR cells within the TME, and the lack of truly tumor-specific antigens. Preclinical studies underscore these challenges, with findings showing that less than 2% of adoptively transferred immune cells reach and infiltrate solid tumors. [ 256 , 257 ] In a prostate cancer model, spatiotemporal imaging of prostate-specific membrane antigen (PSMA)-targeted CAR-T cells revealed extensive off-target accumulation in the thyroid, salivary glands, stomach, and bladder, with only 0.2% of cells localizing to the tumor site. [ 258 ] Improving the tumor-homing efficiency of engineered immune cells may allow for lower therapeutic cell doses while maintaining efficacy, thereby reducing the risk of off-target effects and improving safety. A promising approach involves engineering CAR- or T cell receptor (TCR)-modified helper cells to express specific chemokine receptors or secrete chemokines, enhancing their chemotaxis, tumor targeting, and intratumoral infiltration. IL-8/CXCL8 is frequently overexpressed in several solid tumors, including melanoma, glioblastoma, breast, colon, gastric, and non-small cell lung cancers, and its expression positively correlates with tumor burden. [ 259 , 260 , 261 , 262 , 263 ] Its primary receptors, CXCR1 and CXCR2, have been genetically engineered into tumor-infiltrating lymphocytes or co-expressed with CARs in lymphocytes to improve the efficacy of adoptive cell therapy. [ 264 , 265 ] CAR-T cells expressing CXCR2 exhibit enhanced trafficking, intratumoral accumulation, and antitumor efficacy in xenograft models. [ 266 ] When combined with ionizing radiation, CXCR1/2-modified CAR-T cells (8R70CAR) demonstrate improved migratory and proliferative capacities at tumor sites, resulting in complete regression of advanced-stage tumors, outperforming their unmodified counterparts. [ 267 ] Similarly, CAR-T cells co-expressing CXCR1 or CXCR2 and targeting the αvβ6 integrin display superior therapeutic efficacy and reduced toxicity in ovarian and pancreatic cancer models. [ 268 ] In another approach, CCR4-engineered CAR-T cells based on mogamulizumab specificity selectively depleted Th2 cells and Tregs, while spared CD8 + and Th1 populations. This strategy induced long-term remission in human T-cell lymphoma models and enhanced tumor infiltration by suppressing MDSC migration through the STAT3/nuclear factor kappaB (NF-κB)/SDF-1α axis. [ 269 , 270 ] NK cells have also been optimized through chemokine receptor modification. CXCR1- or NKG2D-engineered NK cells exhibit increased migration toward tumor-derived chemokines in vitro and improved tumor infiltration in xenograft models in vivo . Although cytotoxicity remained unchanged in vitro , co-expression of CXCR1 and a CAR significantly enhanced antitumor activity in vivo . [ 271 ] To improve bone marrow homing, NK cells engineered with both a human CD19-specific CAR (huCAR19) and CXCR4 , termed T cell Redirected for Antigen-specific Cytotoxicity and Kinetics, demonstrated superior migration toward SDF-1 and bone marrow stromal cells, while maintaining potent cytolytic activity compared with conventional CAR-NK cells. [ 272 ] Moreover, CAR-T cells targeting EGFR and co-expressing CXCR5 retained their cytotoxicity in vitro but achieved significantly enhanced infiltration into CXCL13-expressing non-small cell lung tumors, leading to superior tumor eradication in vivo . [ 273 ] Similarly, CAR-T cells engineered to secrete the CCR7 ligand CCL19 promoted sustained intratumoral persistence and recruited endogenous T cells and DCs, further amplifying antitumor responses in preclinical models. [ 274 , 275 , 276 ] Collectively, these studies highlight the therapeutic promise of harnessing chemokine–chemokine receptor axes to improve the trafficking, infiltration, and persistence of adoptive immune cells in solid tumors. This strategy offers a compelling approach to enhance the clinical efficacy of cell-based immunotherapies. Epigenetic Regulation of Chemokine Signaling in the TME Recent studies highlight the crucial role of epigenetic mechanisms, including histone modifications (e.g., histone-3 lysine-27 acetylation [H3K27ac], lysine 27 on histone H3 [H3K27me3]), DNA methylation, and non-coding RNAs, in regulating chemokine expression. In cancer, aberrant epigenetic remodeling suppresses antitumor chemokine expression, contributing to immune evasion and therapy resistance. These findings suggest that reversing such epigenetic changes could restore chemokine-mediated immune responses, thereby enhancing immunotherapy efficacy. In preclinical models, combined inhibition of EZH2 (a histone methyltransferase) with 3-deazaneplanocin (DZNep) and DNMT1 using 5-aza-2′-deoxycytidine increased Th1-type chemokine production, improving the effectiveness of adoptive T-cell therapy and PD-L1 blockade. [ 277 ] CXCR4, a key driver of tumor metastasis, is regulated by both DNA methylation and histone acetylation. Inhibitors such as suberoylanilide hydroxamic acid and trichostatin A can downregulate CXCR4, with trichostatin A showing potential as an anticancer agent. [ 278 , 279 ] Targeting EZH2 and DNMT1 also upregulates CXCL9 and CXCL10, enhancing T cell infiltration and inhibiting tumor progression in ovarian cancer, thereby boosting checkpoint blockade and T-cell therapy efficacy. [ 28 ] Similarly, in CRC, polycomb repressive complex 2 (PRC2)-mediated H3K27me3 deposition (via EZH2, suppressor of Zeste 12 [SUZ12], and embryonic ectoderm development [EED]) epigenetically silences CXCL9/10, limiting T cell infiltration and facilitating immune escape. Reversing this silencing restores Th1 chemokine expression and improves antitumor immunity. [ 280 ] In neuroblastoma, the H3K9 methyltransferases euchromatic histone lysine methyltransferase 2 (EHMT2)/G9a and EHMT1/GLP suppress IFN-γ-induced immune responses, promoting MYCN-driven tumor aggressiveness. Inhibiting EHMTs restores CXCL9/10 expression and T cell recruitment. Notably, dual inhibition of EHMT and EZH2 is required for robust IFN-γ-induced chemokine activation in MYCN-amplified tumors, correlating with epigenetic remodeling at chemokine loci. [ 281 ] Elevated EHMT and EZH2 activity in aggressive neuroblastomas is linked to an immunologically “cold” TME. The pyrimidone compound BR-001 has demonstrated antitumor effects by disrupting the interaction between embryonic ectoderm development protein and H3K27me3, thereby upregulating CXCL10 and enhancing CD8 + T cell infiltration. Furthermore, combined inhibition of EZH2 and histone deacetylases (HDACs) restores interferon-inducible protein 16 (IFI16)-dependent immune activation, leading to complete tumor eradication and long-term memory T-cell responses. [ 282 ] In HER2 + breast cancer, epigenetic activation of the IFI16–CXCL10/11 axis improves CD8 + T cell infiltration and overcomes trastuzumab resistance. [ 283 ] Collectively, these findings suggest that epigenetic modulation can reactivate suppressed chemokines, reprogram the TME, and sensitize tumors to immunotherapy. Specifically, EZH2 inhibitors upregulate CXCL9/10, facilitating T cell infiltration into “cold” tumors. DNA methyltransferase (DNMT) inhibitors demethylate and restore tumor-suppressive chemokines, counteracting CXCR4-driven metastasis. HDAC inhibitors downregulate CXCR4, reducing stromal-mediated drug resistance in pancreatic and breast cancers. CXCR4 antagonists + DNMT inhibitors synergize with ICB by limiting MDSC and Treg recruitment. Hypomethylating agents + anti-CCL2/CCR2 therapy reduce TAM infiltration and enhance immunotherapeutic responses. Thus, combining epigenetic modulators targeting chemokine pathways holds significant promise for overcoming immune resistance and improving cancer immunotherapy outcomes. Epigenetic modifications regulate chemokine gene expression through multiple pathways, serving as reversible switches with promising therapeutic potential for cancer prevention and treatment. Targeting these epigenetic pathways could reverse immune suppression, overcome chemokine-mediated resistance, and reprogram the TME. However, challenges such as off-target effects, delivery issues, TME resistance, and the need for precise patient stratification limit their clinical effectiveness. Further research is crucial to develop reliable methods for assessing immune responses and improving the efficacy of combination therapies. Chemokine-Targeted Therapies: Challenges and Future Perspectives Chemokines have significant potential to overcome tumor immune tolerance by promoting tumor eradication, enhancing immune cell priming, aiding antigen presentation by APCs, and boosting memory T-cell responses. However, their complex pleiotropic effects complicate their use in cancer therapy. A single chemokine can act in both pro- and anti-tumorigenic roles, depending on context, receptor interactions, and spatiotemporal dynamics. Within tumors, chemokine gradients exhibit spatial heterogeneity, shaped by the TME consisting of hypoxic cores, necrotic regions, and stromal-rich zones. These areas regulate chemokine expression differently, creating complex chemotactic fields that vary across the tumor. Additionally, the tumor chemokine landscape evolves over time. Early-stage tumors secrete immunostimulatory chemokines, recruiting NK cells and Th1 cells to initiate immune responses. In contrast, late-stage tumors shift to an immunosuppressive chemokine profile, promoting Treg and MDSC infiltration, thus aiding immune evasion. Therapy-induced changes in chemokine levels further contribute to treatment resistance. For instance, while radiotherapy and chemotherapy increase CXCL10, boosting CD8 + T cell recruitment, they also upregulate CXCL1/CXCL8, promoting resistance through myeloid cell accumulation. ICB alters chemokine balances, increasing CCL5 (which recruits effector T cells) and decreasing CCL22 (which suppresses Tregs), thereby fostering a more favorable antitumor TME. These dynamic, therapy-dependent chemokine shifts underscore the dual roles of chemokines in modulating antitumor immunity and highlight their potential as therapeutic targets. To address these complexities, precise spatiotemporal intervention strategies are essential. Approaches such as targeted delivery systems, viral vectors expressing chemokines, genetically modified DCs, and engineered tumor cells expressing chemokines offer potential for localized disruption of pathological chemokine gradients. Additionally, strategies involving tumor-specific promoters and OVs are being explored for precise chemokine delivery to the TME. Despite the promise of chemokine-targeted therapies, monotherapies using chemokines or chemokine receptors alone remain suboptimal. Combining chemokine or chemokine receptor antagonists with ICIs could help overcome compensatory immunosuppressive mechanisms and enhance the efficacy of monotherapies. Ongoing research into chemokines as adjuvants has shown promising results, with several studies advancing from preclinical to phase I and II clinical trials. Further investigation is needed to identify the most effective chemokines for specific tumor types. Chemokines can induce systemic toxicity, such as cytokine storms, in targeted therapies, emphasizing the risks of broad chemokine-related toxicity. Inappropriate modulation of chemokine networks can disrupt immune tolerance, leading to abnormal T cell trafficking and autoreactivity. Elevated CXCL10 levels in peripheral fluids serve as a biomarker for Th1-driven immune responses. The CXCL10–CXCR3 axis plays a pivotal role in the pathogenesis of various autoimmune disorders, including both organ-specific and systemic conditions. Excessive chemokine signaling, such as elevated CXCL8, can cause uncontrolled leukocyte infiltration and hyperactivation, contributing to cytokine release syndrome. For example, CCR5 antagonists may unintentionally exacerbate inflammation by triggering compensatory chemokine upregulation. Furthermore, the redundancy in chemokine–receptor interactions means that targeting one pathway may activate unintended signaling cascades, while excessive suppression of the chemokine–receptor axis can increase susceptibility to infections. To mitigate these risks, targeted delivery systems, context-specific dosing, and serum cytokine monitoring will be critical in minimizing adverse effects associated with chemokine-modulating therapies. Adoptive immune cell therapy has proven effective for hematologic malignancies, but its success in solid tumors is hindered by challenges in immune cell infiltration and migration. Engineering immune cells to express chemokines or their receptors can enhance the antitumor activity of T cells, NK cells, and macrophages while minimize off-tumor toxicity. Combining chemokine–chemokine receptor targeting with other immunotherapies offers a promising approach to improving tumor treatment. To optimize chemokine delivery, strategies must address their short half-lives and enable controlled, localized release with minimal off-target exposure. Potential solutions include nanoparticles that protect chemokines from degradation and facilitate controlled release, or OVs engineered to express chemokines directly within tumors, avoiding systemic exposure. Genetically modified cell-based therapies can also deliver chemokines locally, reducing off-target effects. The most effective approaches may combine nanoparticles for controlled chemokine release with OVs or engineered cells for localized production, incorporating tumor-targeting and stimuli-responsive mechanisms. These strategies aim to maximize local chemokine activity and minimize systemic side effects. We expect substantial progress in therapies targeting the chemokine–chemokine receptor axis, with advancements in combined immune cell and chemokine-targeting strategies progressing from preclinical studies to clinical trials. Acknowledgements The authors would like to thank Mrs. Ling Li for her exceptional laboratory management. Fundings This work was supported by grants from Shenzhen Medical Research Fund (No. B2302030), the National Natural Science Foundation of China for Key Program (Nos. 32330037 and 81802846), and the National Key Research and Development Program of China (No. 2023YFA0915000). Conflicts of interest None. 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