Lactate signaling and immune suppression in tumors: mechanisms and therapeutic implications.

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Learn more: PMC Disclaimer | PMC Copyright Notice Cell Oncol (Dordr) . 2026 Apr 20;49(3):75. doi: 10.1007/s13402-026-01186-6 Search in PMC Search in PubMed View in NLM Catalog Add to search Show available content in en fr Lactate signaling and immune suppression in tumors: mechanisms and therapeutic implications Xiaodong Wang Xiaodong Wang 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Xiaodong Wang 1 , Di Xiong Di Xiong 2 Department of General Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Di Xiong 2 , Songli Cui Songli Cui 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Songli Cui 1 , Bingchen Duan Bingchen Duan 3 Department of Orthopaedic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Bingchen Duan 3 , Gouping Ding Gouping Ding 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Gouping Ding 1 , Yiping Huang Yiping Huang 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Yiping Huang 1 , Qianqian Wang Qianqian Wang 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China Find articles by Qianqian Wang 1, ✉ Author information Article notes Copyright and License information 1 Department of Oncology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China 2 Department of General Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China 3 Department of Orthopaedic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, China ✉ Corresponding author. Received 2026 Jan 20; Accepted 2026 Mar 1; Collection date 2026 Jun. © The Author(s) 2026 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/ . PMC Copyright notice PMCID: PMC13096266  PMID: 42010177 Abstract Lactate is no longer viewed as a passive end-product of the Warburg effect; instead, it plays an active role in shaping tumor biology and immune responses. In solid tumors, enhanced glycolysis and lactate export, along with proton handling, generate steep lactate and acidosis gradients that exert selective pressure on immune cells. Beyond competition for resources, lactate signals through specific receptors and drives epigenetic changes via lactylation, altering the transcriptional profiles of tumor, stromal, and immune cells. These processes lead to the suppression of cytotoxic T cells and natural killer cells, impair antigen presentation, and promote regulatory T cells and myeloid suppressor cells, which collectively contribute to the development of immune-resistant “cold” microenvironments. Targeting the lactate signaling pathway, whether by inhibiting lactate production, transport, pH buffering, or receptor signaling, provides a promising strategy to counteract metabolic immune suppression. This review integrates recent findings on lactate-driven immune remodeling, identifies potential therapeutic targets, and discusses how these strategies can be combined with immunotherapy and cellular treatments to improve outcomes. We also highlight the need for biomarkers to assess lactate-specific effects and distinguish them from those caused by acidosis. Graphic Abstract Keywords: Lactate, Tumor immune microenvironment, Monocarboxylate transporters, Histone lactylation, Immunotherapy resistance. Introduction Lactate, once viewed as a mere byproduct of anaerobic metabolism, has gained recognition as a central regulator in cancer biology. In tumors, excessive lactate production arises from the Warburg effect, where cancer cells favor aerobic glycolysis and lactate production despite adequate oxygen availability [ 1 – 3 ]. Far from being inert, lactate drives malignancy by enhancing tumor cell survival, invasion, metastasis, and immune evasion, with high intratumoral lactate levels linked to unfavorable outcomes in various solid cancers [ 4 , 5 ]. Acting as both a signaling molecule and an energy source in the tumor microenvironment, lactate influences the dynamics of malignant, stromal, and immune cells, prompting exploration of lactate-targeted therapies [ 6 ]. Metabolic reprogramming stands as a defining feature of cancer, profoundly shaping the tumor immune microenvironment (TIME) [ 7 ]. Driven by oncogenes and hypoxia, this shift leads cancer cells to convert glucose to lactate, yielding rapid ATP production through glycolysis while channeling intermediates into anabolic pathways [ 8 , 9 ]. Such adaptations enable tumors to endure variable oxygen and nutrient conditions but result in lactate buildup. During early tumor development, infiltrating immune cells can initiate antitumor responses; however, as tumors expand, the glycolytic and hypoxic environment imposes metabolic stresses on leukocytes. Accumulating lactate and associated acidosis impair effector immune cell function or redirect their programs, while promoting immunosuppressive populations [ 10 , 11 ]. Given that lactate export often coincides with proton extrusion, distinguishing the effects of the lactate anion from those of low pH remains challenging, though both interact synergistically in tumors to promote progression [ 12 – 14 ]. The TIME in solid cancers encompasses adaptive and innate immune cells, stromal components, vessels, and extracellular matrix, forming metabolically diverse compartments. Here, elevated lactate serves as a key immunomodulator, connecting tumor metabolism to immune suppression and enabling escape from surveillance [ 15 , 16 ]. By altering metabolism, differentiation, and activity across cell types, lactate and acidity transition the microenvironment from an inflammatory, antitumor state to one that supports tumor persistence [ 17 ]. Thus, cancer cell metabolic alterations and the ensuing lactate-rich, oxygen-deprived conditions are intricately linked to TIME organization and function. Emerging evidence also suggests that host metabolic states, such as obesity induced by high-fat diets, can exacerbate intratumoral lactate levels, further reprogramming the TIME and hastening progression [ 18 – 20 ]. The intertwined roles of lactate in tumor metabolism and immune control underscore its potential as a therapeutic target. While immune checkpoint inhibitors have revolutionized oncology, their benefits are limited in immunologically cold tumors. Lactate excess is increasingly implicated in this resistance, and interventions that curb lactate generation or efflux have shown promise in restraining tumor growth and augmenting immunotherapy in experimental systems [ 21 , 22 ]. This review explores lactate as a metabolite and signaling agent in solid tumors, emphasizing its impact on antitumor immunity. We outline the factors governing lactate generation, spatial distribution, and signaling within tumors; dissect how lactate reshapes immune cell subsets in the TIME to facilitate immune evasion; evaluate approaches to inhibit lactate metabolism or transport, or to engineer immune cells resilient to high-lactate settings; and address biomarkers, translational methodologies, and unresolved issues in advancing metabolic-immune interventions. Lactate metabolism and signaling in the tumor context Cellular and molecular determinants of lactate production and transport Aerobic glycolysis serves as the primary source of lactate in tumors [ 3 ]. Glucose undergoes conversion to pyruvate, which lactate dehydrogenase (LDH) reduces to lactate, concurrently regenerating NAD⁺ 3,11 . Tumors predominantly express the LDHA isoform, favoring pyruvate-to-lactate transformation, in contrast to LDHB, which prevails in oxidative tissues and supports the opposing reaction; elevated LDHA expression correlates with heightened lactate levels and adverse prognosis [ 4 , 5 , 11 ]. Tumor cells also direct glutamine through the tricarboxylic acid cycle toward pyruvate and lactate production, such that integrated reprogramming of glucose and glutamine metabolism—bolstered by transcriptional, post-transcriptional, and post-translational LDH activation, including LDHA acetylation—sustains hyperactive glycolysis and robust lactate generation in cancer [ 3 , 8 , 23 ] (Fig. 1 ). Fig. 1. Open in a new tab Tumor lactate production, export, and spatial gradients across metabolic niches. Schematic overview of lactate generation and handling in solid tumors. Oncogene- and hypoxia-driven aerobic glycolysis increases pyruvate-to-lactate conversion via LDH (typically LDHA-biased), with concurrent NAD⁺ regeneration. Lactate is exported together with protons primarily through monocarboxylate transporters (MCTs), with MCT4 enriched in hypoxic/glycolytic cancer regions and MCT1 prevalent in more oxygenated tumor or stromal compartments to support lactate shuttling. Carbonic anhydrases and complementary proton exchangers reinforce extracellular acidification, producing steep lactate–pH gradients from necrotic/hypoperfused cores to vascularized margins that differentially constrain effector immunity while favoring suppressive cell states To mitigate intracellular acid burden, cancer cells expel lactate through proton-linked monocarboxylate transporters MCT1 and MCT4 9 . MCT4 undergoes marked induction in glycolytic, hypoxic tumor cells, functioning as the principal efflux conduit, while MCT1 enriches in oxygenated tumor and stromal compartments, enabling lactate shuttling across cellular domains [ 3 , 9 ]. Chaperone proteins like CD147 enhance MCT stability and membrane localization [ 9 ]. Numerous tumors simultaneously elevate carbonic anhydrase IX and other proton exchangers to maintain intracellular pH homeostasis, albeit intensifying extracellular acidosis [ 13 , 14 ]. This culminates in extracellular lactic acid abundance, reaching millimolar concentrations well beyond physiological norms [ 4 ]. Pronounced lactate gradients emerge, peaking in hypoperfused tumor cores and diminishing at vascularized margins; co-export of lactate and protons via MCTs intimately ties lactate accrual to extracellular acidification [ 3 , 13 ]. Carbonic anhydrases and supplementary proton pumps amplify this lactic acidosis, forging acidic, lactate-saturated niches seldom found in normal tissues [ 14 ]. Most antitumor effector populations, such as T and NK cells, exhibit metabolic compromise under these conditions, whereas immunosuppressive lineages—including tumor-associated macrophages and regulatory T cells—adapt or thrive preferentially [ 10 , 11 , 15 ]. As a result, immune infiltrates in varied tumor zones encounter disparate metabolic hurdles, rendering interventions that modulate lactate or pH especially promising for equilibrating hypoxic interiors, enhancing effector T-cell infiltration depth, and surmounting regionally confined immune restraint in preclinical models. Spatial and temporal features of lactate accumulation in solid tumors Solid tumors exhibit pronounced spatial heterogeneity in oxygen and nutrient distribution [ 24 ]. As tumors expand beyond their vascular supply, central zones turn hypoxic and adopt glycolytic metabolism, intensifying local lactate generation [ 3 , 25 ]. This fosters steep gradients of lactate and protons, with peak concentrations in hypoperfused, necrotic cores and diminished levels at oxygenated invasive fronts [ 3 ]. Lactate efflux through MCT1 and MCT4 transporters links its accumulation to pericellular acidification [ 9 ]. Stromal proton-handling mechanisms, such as carbonic anhydrases, further acidify the extracellular milieu, creating dynamic pockets of lactic acidosis that vary with fluctuations in perfusion and metabolic activity [ 13 , 26 ]. These lactate-enriched niches impose selective pressures: cytotoxic lymphocytes typically perform best at near-physiological pH and minimal lactate, while regulatory and myeloid cells endure or flourish in acidic, high-lactate environments [ 10 , 11 , 15 ]. Tumor metabolic adaptation over time, including enhanced glycolysis amid therapy-driven hypoxia, can amplify lactate buildup [ 3 ]. Serial imaging and metabolomic analyses reveal that lactate abundance and patterning evolve during therapy, associating with emergent immune resistance [ 3 , 5 ]. Such spatiotemporal dynamics highlight the imperative for therapies that penetrate all tumor compartments and respond to metabolic adaptations. Lactate as a signaling entity Lactate serves not only as a metabolite but also as a ligand for G-protein-coupled receptors [ 27 ]. The most well-characterized receptor is GPR81 (also termed HCAR1), a Gi-coupled receptor present on both tumor and immune cells [ 28 ]. Binding of lactate to GPR81 reduces intracellular cAMP levels and triggers pro-survival and pro-angiogenic cascades, operating through autocrine and paracrine loops in the tumor microenvironment [ 17 , 29 ]. Other receptors detect lactate or associated signals in myeloid cells: GPR132 (G2A) senses pH alterations linked to lactate and facilitates tumor-macrophage interactions, while GPR65 (TDAG8), a proton-sensing receptor upregulated on tumor-associated macrophages, activates in acidic, lactate-laden settings to engage cAMP/PKA/CREB pathways that drive immunosuppressive factor secretion and invasiveness [ 30 – 32 ]. These receptors enable immune cells to differentiate signals from the lactate anion (via GPR81) versus low pH (via GPR65), underscoring that both the metabolite and acidity can autonomously influence immune responses [ 28 , 33 ]. In T cells, lactate-GPCR signaling modulates checkpoint molecule expression and lineage commitment; for instance, GPR81 activation on CD8⁺ T cells associates with PD-1 downregulation and effector dysfunction in lactate-rich milieus [ 17 , 34 ]. In contrast, GPR65 stimulation on macrophages promotes polarization toward suppressive states [ 32 ]. Histone lactylation represents another avenue for lactate-mediated signaling. This epigenetic modification involves the addition of lactyl groups—derived from lactate—to lysine residues on histones, catalyzed by the acetyltransferase p300, with removal mediated by specific histone deacetylases [ 35 – 37 ]. By modulating chromatin accessibility, histone lactylation reprograms gene expression: in classically activated (M1) macrophages, lactic acid buildup induces lactylation marks that shift transcriptional output toward wound-healing and M2-like phenotypes [ 35 , 37 ]. In cancer cells, lactylation of histones and non-histone proteins correlates with attributes like stemness and immune evasion [ 38 ]. Both tumor cells and resident immune populations within the TIME display lactylation signatures, suggesting this modification affects diverse cellular compartments [ 39 ]. Lactate can further lactylate and stabilize select transcription factors in immune cells, altering their regulatory roles [ 40 ]. Consequently, lactate-induced epigenetic changes impose lasting effects on gene regulation, promoting regulatory T cell and tolerogenic dendritic cell maturation while dampening effector programs; such alterations may prove amenable to reversal through inhibitors of lactylation enzymes [ 34 , 41 ](Fig. 2 ). Fig. 2. Open in a new tab Lactate as an immunometabolic signal: receptor-mediated sensing and lactylation-dependent epigenetic remodeling. Diagram of principal lactate-sensing and response pathways within the tumor microenvironment. Extracellular lactate engages GPCRs (e.g., GPR81/HCAR1) and cooperates with acidity sensed by proton-responsive receptors (e.g., GPR65), shaping cAMP-linked signaling and downstream programs that tune immune activation, polarization, and checkpoint regulation. In parallel, lactate fuels covalent protein/histone lactylation (e.g., via p300) with removal by delactylase activity (HDACs), reprogramming transcriptional circuits in tumor and immune cells. These signaling layers interface with canonical stress and inflammatory pathways (e.g., HIF-1α and NF-κB), collectively converting metabolic inputs into durable immune-regulatory phenotypes In addition to GPCR engagement and lactylation, lactate activates further pathways that bridge metabolism and immunity. It can stimulate NF-κB and HIF-1α in immune cells, where it stabilizes HIF-1α by inhibiting prolyl hydroxylases, thereby enhancing HIF-target gene transcription (including VEGF, arginase-1, and glycolytic enzymes) [ 15 , 42 , 43 ]. Lactate also represses proline dehydrogenase to avert apoptosis, facilitates a metabolic lactate shuttle between cancer-associated fibroblasts and tumor cells that ties to IL-6 production, and sustains kynurenine pathway-mediated tryptophan degradation in plasmacytoid dendritic cells [ 41 , 44 ]. Collectively, these mechanisms establish lactate as a pivotal orchestrator of metabolic interplay and immune modulation within the tumor ecosystem. Immunomodulatory actions of lactate in the tumor immune microenvironment Adaptive lymphocytes: constraining effector functions and shaping lineage fate Cytotoxic T lymphocytes and natural killer cells represent principal effectors of antitumor immunity yet face metabolic constraints from elevated lactate within the tumor immune microenvironment (see Table 1 ). High lactate attenuates NFAT signaling in both populations, diminishing interferon-γ and other cytokine production while eroding cytotoxic capabilities [ 10 , 11 ]. It further perturbs T-cell metabolism: rather than facilitating balanced mitochondrial pyruvate utilization via pyruvate carboxylase and pyruvate dehydrogenase, surplus lactate redirects pyruvate flux through PDH in a disordered fashion, leading to intermediate buildup and an energy shortfall that hampers effector performance; PDH blockade can reinstate function [ 45 – 47 ]. Lactate inhibits glucose uptake in T cells by engaging GLUT1, restricting glucose influx and effectively depriving activated T cells of fuel [ 48 ]. As a result, CD8⁺ T cells in lactate-abundant tumors display curtailed proliferation, lowered perforin and granzyme levels, and heightened vulnerability to activation-induced apoptosis, as evidenced in KRAS-mutant colorectal cancer models, whereas tumor lactate reduction bolsters CD8⁺ T-cell ingress and augments checkpoint inhibition outcomes [ 11 , 17 , 34 ]. NK cells encounter analogous impairments: in acidic, lactate-saturated settings, they suppress activating receptors and cytotoxic effectors, exhibit defective target lysis, respond to lactate through GPR81 with curtailed perforin and granzyme B expression, and may succumb to lactic acidosis-triggered mitochondrial apoptosis, collectively fostering immune evasion [ 11 , 16 ]. While transient lactate exposure can, in defined contexts, augment CD8⁺ T-cell stemness and bolster adoptive cell therapy efficacy, persistent high lactate in tumors chiefly represses CTL and NK activity [ 46 ]. Accordingly, lactate also directly hampers additional innate lymphoid subsets. Group 1 ILCs (ILC1-like cells) under lactic acidosis demonstrate reduced proliferation and IFN-γ output alongside elevated PD-1 expression, and group 2 ILCs (ILC2s) likewise manifest subdued cytokine release (such as IL-5), proliferation, and viability in high-lactate milieus [ 49 , 50 ]. The erosion of these innate effectors exacerbates the scarcity of type 1 cytokines and impairs auxiliary immune cell recruitment (including eosinophils) in lactate-enriched tumors. Table 1. Lactate-mediated modulation of major immune cell populations in the TIME Immune cell type Lactate source / uptake Core metabolic / epigenetic effect Key functional changes Main receptors / pathways Net impact on antitumor immunity Reference CD8⁺ cytotoxic T cells (CTLs) Lactate-rich TIME generated mainly by glycolytic tumor cells (hypoxic cores) and stromal sources (e.g., CAFs); uptake via MCT1/MCT11 Lactate flux and/or lactic acidosis perturbs glycolysis–pyruvate coupling, redox balance, and nutrient availability for effector programs ↓ Proliferation; ↓ IFN-γ/perforin/granzyme; ↑ dysfunction/AICD; reduced efficacy of ICB/ACT MCT1/MCT11, NFAT inhibition, PDH/mitochondrial flux stress, acidic pH stress responses Suppresses CTL fitness, infiltration and tumor control Activation and antitumor immunity of CD8(+) T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid [ 51 ]; Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism [ 45 ]. NK cells Lactate-rich and acidic tumor niches (often hypoxic regions) Lactic acidosis induces mitochondrial stress and apoptosis; lactate signaling can dampen cytotoxic programs ↓ Activating receptors; ↓ perforin/granzyme B; impaired killing; ↑ apoptosis GPR81/HCAR1-linked signaling; MCT-associated lactate handling; mitochondrial apoptosis pathways Weakens innate cytotoxic surveillance; promotes metastasis Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis [ 52 ]; LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells [ 11 ]. Innate lymphoid cells (ILC2) Tumor-derived lactate accumulation in TIME (melanoma model); local acidic niches Lactate attenuates ILC2 function and survival in tumors ↓ ILC2 abundance and effector activity; impaired IL-33/ILC2/eosinophil antitumor axis Lactate/acid stress–linked suppression (tumor-context dependent) Reduces ILC2-mediated antitumor support Tumor-Derived Lactic Acid Contributes to the Paucity of Intratumoral ILC2s [ 49 ]. CD4⁺ Th1 / effector T cells Lactate produced by tumor and stromal glycolysis Metabolic stress interferes with glycolytic reprogramming required for Th1 differentiation/effector function ↓ IFN-γ–producing Th1 cells; skewing away from pro-inflammatory helper phenotypes Acidic pH stress responses; lactate-linked suppression of T-cell effector programs Weakens pro-inflammatory CD4⁺ help for CTL/NK responses LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells [ 11 ]; Overcoming T cell dysfunction in acidic pH to enhance adoptive T cell transfer immunotherapy [ 53 ] Regulatory T cells (Tregs) High lactate microdomains in tumors; uptake via MCT1 Tregs can use lactate as fuel; supports Foxp3 stability/survival; reinforces suppressive programs ↑ Foxp3; ↑ CTLA-4/IL-10; enhanced suppressive capacity and stability; accumulation in tumors MCT1; lactate-driven signaling; PD-1 upregulation reported Strengthens immunosuppressive compartment Metabolic support of tumour-infiltrating regulatory T cells by lactic acid [ 54 ]; Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments [ 34 ]. Dendritic cells (cDCs, pDCs) Tumor-derived lactic acid; uptake via MCT1 Reprogramming toward tolerogenic programs; impaired maturation and antigen presentation/cross-priming ↓ MHC-II/CD80/CD86/IL-12; ↑ IL-10; enhanced Treg induction; pDC pro-tumor reprogramming Lactate–SREBP2 axis, lactate-induced tolerogenic DC programs Blunts priming of tumor-specific T cells A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression [ 55 ]; Lactate Induces Pro-tumor Reprogramming in Intratumoral Plasmacytoid Dendritic Cells [ 41 ]. Tumor-associated macrophages (TAMs) High local lactate from hypoxic tumor cores Lactate drives protumoral polarization programs; lactate sensing promotes metastasis-associated macrophage functions M2-like polarization; ↑ angiogenesis/matrix remodeling; pro-metastatic cytokine/chemokine outputs Lactate-driven polarization; Gpr132 lactate sensing–dependent tumor–macrophage interplay Builds protumoral myeloid niche; suppresses T cells Functional polarization of tumour-associated macrophages by tumour-derived lactic acid [ 15 ]; Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis [ 30 ]. Myeloid-derived suppressor cells (MDSCs) Lactate-rich TIME; lactate can promote recruitment and suppressive programming Enhances suppressive metabolism and pro-ROS/arginase programs ↑ Accumulation; ↑ ROS/arginase; ↑ suppression of T-cell proliferation; therapy resistance Lactate-driven myeloid suppression programs (model-dependent) Reinforces suppressor network and immune resistance Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells [ 16 ]. Open in a new tab Note: TIME, tumor immune microenvironment; CAF, cancer-associated fibroblast; CTL, cytotoxic T lymphocyte; NK, natural killer; ILC, innate lymphoid cell; Th1, T helper 1; Treg, regulatory T cell; DC, dendritic cell; cDC, conventional dendritic cell; pDC, plasmacytoid dendritic cell; TAM, tumor-associated macrophage; MDSC, myeloid-derived suppressor cell; TME, tumor microenvironment; MCT, monocarboxylate transporter; GPR81/HCAR1, hydroxycarboxylic acid receptor 1; IFN-γ, interferon-γ; AICD, activation-induced cell death; PDH, pyruvate dehydrogenase; HIF-1α, hypoxia-inducible factor 1-alpha; CTLA-4, cytotoxic T-lymphocyte–associated protein 4; IL, interleukin; ROS, reactive oxygen species; Arg1, arginase-1; MHC-II, major histocompatibility complex class II. “Reference (Title)” lists only primary/original research articles that directly support the indicated lactate-associated phenotype or mechanism; review articles were excluded Lactate further reorients CD4⁺ T-cell dynamics toward immunosuppression. In lactate-laden environments, helper T cells deviate from Th1 commitment toward regulatory T cells, with lactate diminishing IFN-γ-secreting Th1 cells while amplifying NF-κB activation and Foxp3 expression in naive CD4⁺ T cells [ 48 , 56 ]. Tumor-resident Tregs adapt metabolically to exploit lactate: robust MCT1 expression permits lactate uptake as both substrate and cue, elevating Foxp3 abundance, reinforcing lineage fidelity, and, through deubiquitinase USP39 induction, heightening CTLA-4 synthesis and suppressive potency [ 34 , 57 , 58 ]. Lactate-rich, acidic zones also enlarge the Treg pool by recruiting Tregs and prompting conventional CD4⁺ T cells to adopt regulatory traits—for instance, influenced by lactate-producing cancer-associated fibroblasts [ 15 , 59 ]. Lactate variably regulates immune checkpoints, promoting NFAT nuclear entry and PD-1 upregulation in Tregs while counterintuitively curbing PD-1 on CD8⁺ T cells, thus tilting equilibrium toward suppressive elements [ 17 , 34 ]. Lactate-primed Tregs, marked by elevated CTLA-4 and IL-10, predominate in the CD4⁺ niche across numerous tumors, directly restraining CD8⁺ T and NK cells while fostering M2-like macrophage skewing [ 57 , 58 ]. Hence, lactate within the tumor immune microenvironment undermines cytotoxic assault and fortifies regulatory barriers, rendering high-lactate tumors largely impervious to primary adaptive immune surveillance. Antigen-presenting cells: dampening initiation of antitumor immunity Dendritic cells require a mature, immunostimulatory profile, characterized by elevated MHC expression, ample co-stimulatory molecules, and IL-12 secretion, to effectively activate naive T cells against tumor antigens. Within a lactate-enriched tumor microenvironment, however, DCs falter in attaining or sustaining this configuration [ 28 , 60 , 61 ]. Lactic acid directly hampers DC maturation and antigen presentation, diminishing surface MHC class II and CD80/CD86 levels while substantially impairing cross-presentation of exogenous antigens to CD8⁺ T cells [ 55 , 60 ]. In vivo, DCs residing in lactate-abundant tumors exhibit flawed priming of cytotoxic T cells, culminating in attenuated effector responses [ 28 ]. These disruptions stem partly from lactate detection via GPR81 on conventional DCs: lactate-GPR81 interaction suppresses MHC class II expression and proinflammatory cytokines, redirecting secretion from IL-12 toward IL-10 and thereby tilting local immunity toward tolerance [ 28 , 41 , 60 ]. Lactate further reprograms DC metabolism [ 41 ]. Plasmacytoid DCs import lactate through MCT1, which augments tryptophan degradation via the immunosuppressive kynurenine pathway and indirectly fosters regulatory T-cell proliferation [ 41 , 62 ]. Moreover, lactate stimulates sterol regulatory element-binding protein 2 (SREBP2) in DCs, propelling their maturation into CD63⁺ regulatory DCs that display compromised cross-presentation and actively elicit Tregs [ 55 , 62 ]. Consequently, despite tumor antigen availability, lactate steers DCs toward tolerogenic trajectories, yielding ineffective or muted T-cell priming [ 55 ]. By debilitating DCs and other antigen-presenting cells, such as tumor-associated macrophages—reoriented by lactate to an anti-inflammatory, arginase-1⁺, IL-10⁺ phenotype—lactate erodes antitumor immunity at its inception [ 15 , 30 ]. This results in diminished generation of tumor-specific T cells, with surviving clones receiving suboptimal or biased cues that promote anergy or regulatory states, permitting unchecked tumor progression. Myeloid suppressor networks: reinforcing immunosuppressive circuits Tumor-associated macrophages often constitute the predominant leukocyte infiltrate in solid tumors, exhibiting a spectrum from proinflammatory M1-like to immunosuppressive M2-like phenotypes. Tumor-derived lactate potently biases polarization toward the M2-like state [ 15 , 63 ]. Lactate uptake through monocarboxylate transporters engages an MCT-HIF-1α axis in macrophages, stabilizing HIF-1α and eliciting M2-linked transcriptional and metabolic shifts [ 15 ]. Lactate-treated macrophages elevate CD206, arginase-1, and IL-10 expression while suppressing IL-12 59 ; in LKB1-mutant lung adenocarcinoma models, MCT4-mediated lactate efflux orients infiltrating macrophages toward M2-like traits and disrupts local T-cell activity, whereas MCT4 ablation counters this skew and augments anti-PD-1 efficacy [ 64 , 65 ]. Lactate further signals via GPR65 on macrophages, triggering cAMP/PKA/CREB cascades that facilitate HMGB1 and other mediator release (including TGF-β and CCL17), thereby bolstering tumor progression and immune dampening [ 30 , 66 ]. Exosomal interchange adds complexity: breast cancer TAMs convey the lncRNA HISLA to neoplastic cells, stabilizing HIF-1α, intensifying glycolysis, and conferring apoptosis resistance, while tumor lactate reciprocally induces HISLA in TAMs, perpetuating HIF-1α activation across compartments [ 15 , 65 , 67 ]. Lactate also heightens reactive oxygen species in TAMs, propelling M2 polarization and, through NLRP3 inflammasome engagement, sustaining chronic immunosuppression [ 68 ]. These M2-skewed TAMs thwart T cells via arginine exhaustion, PD-L1 and IL-10 upregulation, and promote vascularization and extracellular matrix restructuring [ 15 ]. Myeloid-derived suppressor cells are similarly molded by lactate [ 16 ]. In tumor models, elevated lactate prompts neoplastic secretion of CCL2 and CCL7, recruiting CCR2⁺ MDSCs, with tumor MCT4 expression amplifying their accrual [ 16 , 69 ]. Lactate binding to GPR81 on MDSCs activates mTOR/HIF-1α/STAT3 signaling, elevating S100A9 and matrix metalloproteinases while enhancing MDSC-driven therapeutic resistance (such as to radiotherapy) [ 16 , 69 ]. Lactate additionally escalates reactive oxygen species through SGK1 kinase, fortifying MDSC suppression of T-cell expansion via oxidants, arginase, and inhibitory cytokines [ 69 , 70 ]. Together, lactate-orchestrated TAM and MDSC circuits forge a reinforcing myeloid suppressor barrier, an immunosuppressive bulwark that mediates immunotherapy refractoriness and positions these cascades as compelling therapeutic foci. Integrated consequences for TIME architecture As illustrated in Fig. 3 , lactate reshapes the tumor immune microenvironment, fostering immunologically cold tumors that elude immune surveillance and withstand therapeutic interventions [ 11 , 15 ]. Elevated lactate and accompanying acidosis curtail infiltration and functionality of CD8⁺ T cells and NK cells, alongside other type 1 innate lymphoid cells (e.g., ILC1-like cells), while amplifying regulatory T-cell populations and redirecting macrophages and neutrophils toward protumoral orientations [ 11 , 34 ]; concurrently, this elevates immunosuppressive factors including IL-10, TGF-β, and adenosine [ 15 ]. Clinically, heightened serum LDH levels—serving as a proxy for tumor glycolytic activity—correlate with diminished responses to checkpoint inhibition [ 71 ]. Mechanistic investigations reveal that tumor lactate buildup restricts T-cell penetration, induces activation-triggered apoptosis in CD8⁺ T cells, and attenuates anti-PD-1 effectiveness [ 45 , 72 ]; conversely, lactate depletion reinstates T-cell ingress and tumor restraint [ 64 ]. Lactate-maintained regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells forge a self-perpetuating suppressive milieu that repels or neutralizes incoming immune effectors, thereby impairing antigen presentation and effector activities even post-cytotoxic regimens [ 15 , 34 , 69 ]. As a result, lactate-abundant tumors exhibit deficient interferon-enriched, T-cell-inflamed profiles, instead featuring hypoxia, angiogenic, and macrophage hallmarks that foretell immunotherapy refractoriness [ 3 , 64 ]. This lactate-orchestrated condition endures, with metabolic interplay and persistent tumor glycolysis sustaining immune dampening and constraining gains from antigen-liberating therapies [ 11 ]. Preclinical evidence endorses integrating metabolic reprogramming with checkpoint blockade to revive effector capabilities and augment tumor eradication [ 11 , 64 ]. Accordingly, modulating lactate metabolism emerges as a cogent approach to erode the lactate-fueled immunosuppressive barrier and substantially elevate treatment efficacy. Fig. 3. Open in a new tab Integrated remodeling of the tumor immune microenvironment by lactate and therapeutic interception points. Conceptual model summarizing how lactate accumulation and accompanying acidosis restructure TIME architecture into immunologically “cold” states. High lactate suppresses cytotoxic lymphocyte infiltration/function, promotes regulatory T-cell fitness, biases myeloid polarization (e.g., TAM/MDSC protumoral programs), and impairs antigen presentation, thereby reinforcing resistance to immunotherapy. Interventional nodes are mapped along the lactate cascade, including inhibition of lactate production (glycolysis/LDH), blockade of transport (MCTs), buffering/pH modulation, receptor antagonism, lactylation-targeted approaches, and engineering of lactate-resilient immune cells; these strategies are positioned as rational partners to checkpoint blockade and cellular immunotherapies Therapeutic targeting of lactate pathways to potentiate antitumor immunity Inhibition of lactate production Targeting glycolysis through inhibition of lactate dehydrogenase (LDH), especially the LDHA isoform responsible for tumor lactate generation, offers a means to perturb cancer metabolism. Oxamate, a pyruvate mimetic and classical inhibitor, curtails lactate efflux and restrains tumor expansion; in gastric cancer, combining oxamate with trastuzumab surmounts MET-mediated resistance [ 73 , 74 ], while in non-small cell lung cancer, it augments radiosensitivity by depleting intracellular lactate [ 75 ]. FX11, another LDHA antagonist, diminishes lactate release in pancreatic cancer, thereby restricting IL-6 secretion from cancer-associated fibroblasts, mitigating protumoral stromal remodeling [ 76 , 77 ], and suppressing angiogenesis and migration in prostate, breast, and related malignancies [ 78 , 79 ]. Stiripentol, an antiepileptic agent capable of penetrating the blood-brain barrier, inhibits LDH and demonstrates efficacy against glioblastoma when paired with temozolomide or irradiation, reducing lactylation of DNA repair proteins and heightening tumor cell vulnerability to genotoxic stress [ 80 , 81 ]. Other glycolytic checkpoints prove amenable to intervention. Dichloroacetate suppresses pyruvate dehydrogenase kinase, channeling pyruvate into mitochondrial oxidation, elevating tumor pH, and yielding antitumor and immune-reinvigorating outcomes, though it may concurrently favor regulatory T-cell expansion and IL-10 production at the expense of interferon-γ in human T cells [ 82 – 84 ]. The glucose analog 2-deoxy-D-glucose impedes hexokinase activity, attenuating lactate accumulation and lactylation while restoring lenvatinib responsiveness in hepatocellular carcinoma [ 85 , 86 ]. Diclofenac, unexpectedly, lowers tumor lactate levels, bolsters dendritic cell functionality, diminishes regulatory T-cell abundance in models, and potentiates anti-CTLA-4 and anti-PD-1 therapies [ 87 , 88 ]. Given that broad glycolytic inhibition risks disrupting normal tissues and immune homeostasis, subsequent strategies should prioritize tumor-specific isoforms and targeted delivery systems to localize lactate-directed agents within neoplasms and attenuate off-target effects. Blockade of lactate transport and modulation of tumor acidosis Inhibiting lactate transport and tumor acidosis reshapes the metabolic landscape of tumors and can restore antitumor immunity [ 11 , 15 ]. Monocarboxylate transporters MCT1 and MCT4 represent central nodes in this network: their blockade confines lactate within tumor cells, averting its buildup in the extracellular milieu, thereby restricting tumor expansion and preserving pH-sensitive lymphocytes [ 3 , 25 ]. The first-in-class MCT1 inhibitor AZD3965 has entered early-phase trials across malignancies, underpinned by preclinical models showing tumor growth restraint, bolstered T-cell function, heightened radiosensitivity, and, in multiple myeloma, lowered systemic lactate coupled with reduced suppressive myeloid and regulatory T-cell populations [ 89 – 91 ]. Activated effector T cells also employ MCT1 and may proliferate less under non-selective MCT1/2 inhibition, yet regulatory T cells exhibit pronounced dependence on lactate uptake, yielding a therapeutic window that selective agents like 7-ACC leverage to preferentially impair regulatory T cells while sparing conventional T cells and enhancing anti-PD-1 responses [ 34 , 54 , 58 ]. MCT4 prevails as the primary lactate exporter in highly glycolytic, hypoxic tumors; inhibitors such as VB124 amplify T-cell activity and synergize with PD-1/PD-L1 blockade, with high MCT4 expression denoting tumors prone to checkpoint resistance [ 64 , 92 ]. Beyond transport, lactate functions as an immunosuppressive cue: MCT inhibition can mitigate lactate-triggered PD-L1 induction on myeloid cells, and antagonism of the lactate receptor HCAR1 (GPR81) with repurposed agents like reserpine diminishes myeloid-derived suppressor cell recruitment, revives CD8⁺ T-cell functionality, and augments anti-PD-1 efficacy in colorectal cancer models [ 17 , 28 , 30 ]. Tumor acidosis can likewise be addressed directly. Systemic buffering with oral sodium bicarbonate or comparable pH-modulating formulations elevates intratumoral pH, curbs metastasis, and reinvigorates natural killer and cytotoxic T-cell responses, restoring interferon-gamma production and NK cell-driven tumor control in lymphoma [ 14 , 93 , 94 ]. Early clinical findings suggest that high-dose proton pump inhibitors and systemic buffers can potentiate chemotherapy, for example, proton pump inhibitors in metastatic cancers and sodium bicarbonate in liver cancer [ 95 , 96 ]. Buffering approaches and pharmacologic pH modulation via proton pump inhibitors and carbonic anhydrase IX antagonists are being assessed as adjuncts to checkpoint blockade, promoting tumor-infiltrating lymphocyte accumulation and interferon-gamma output during PD-1 inhibition or adoptive T-cell transfer [ 62 , 97 ]. Although chronic buffering or proton pump inhibition may provoke electrolyte disruptions and gastrointestinal toxicity, preclinical evidence—including enhanced chimeric antigen receptor T-cell performance with MCT1 blockade in leukemia—supports merging pH-modulating strategies with immunotherapy as practical and efficacious [ 62 , 90 , 98 ]. Engineering lactate-resilient immune cells Genetic and metabolic engineering of immune cells provides a promising route to counteract the immunosuppressive effects of lactate-enriched tumor environments. Effector lymphocytes can be tailored to endure acidosis, harness lactate, or evade its inhibitory influences [ 10 , 48 ]. For instance, MCT4 knockdown in chimeric antigen receptor (CAR) T cells or overexpression of proton-extruding pumps could bolster their performance in acidic domains [ 64 ]. T cells engineered to lack MCT11 (SLC16A11) demonstrate enhanced cytokine secretion, cytolytic capacity, and responsiveness to PD-1 blockade by preventing lactate excess [ 45 , 54 ]. Armored CAR T cells designed to release IL-12 or IL-18 upon antigen recognition can restructure the microenvironment, repolarizing macrophages from M2 to M1 states and thereby mitigating lactate’s effects on tumor-associated macrophages [ 99 , 100 ]. More targeted approaches involve equipping T cells with lactate oxidase to transform lactate into pyruvate and hydrogen peroxide, depleting local lactate reserves while inflicting oxidative damage on neoplastic cells [ 101 , 102 ]; nanoparticle-mediated lactate oxidase delivery to tumors curbs angiogenesis and favors M1 macrophage skewing, though potential hydrogen peroxide toxicity may necessitate concurrent expression of scavenging enzymes [ 76 , 103 ]. Further prospects encompass disrupting lactate-triggered suppressive pathways, such as metabolite-induced PD-1 upregulation on regulatory T cells, or altering lactate-responsive chromatin via histone deacetylase inhibitors, despite the broad systemic implications of such agents [ 34 – 36 ]. Ultimately, integrating adoptive cell therapy with metabolic modifiers can alleviate acidosis and alleviate resource rivalry. These innovations pave the way for lactate-resilient, and potentially lactate-insensitive, engineered lymphocytes, as illustrated by MCT11-deficient T cells suited for metabolically adverse solid tumors. Synergy with immune checkpoint blockade and cellular immunotherapies Given lactate’s pivotal contribution to immune evasion, pairing lactate-directed therapies with immunotherapies offers a logical means to transform resistant tumors into responsive entities (Fig. 3 ). Preclinical investigations indicate that suppressing lactate synthesis or transport can convert immunologically cold tumors into hot ones amenable to checkpoint inhibition [ 11 , 64 ]. In LKB1-mutant lung cancer, which often defies PD-1 blockade owing to elevated lactate and scant lymphocyte infiltration, tumor-targeted MCT4 silencing augments T-cell penetration and empowers anti-PD-1 to induce regression [ 11 , 46 , 64 ]. Similarly, genetic or chemical LDHA inhibition in glycolytic colon carcinomas elevates intratumoral CD8⁺ T-cell numbers and, when combined with anti-PD-1, yields superior tumor containment relative to monotherapy [ 11 , 34 ]. In melanoma, adjunctive use of the regulatory T cell-selective lactate uptake inhibitor 7-ACC alongside anti-PD-1 elicits regressions beyond those achieved singly, by selectively undermining regulatory T cell suppression [ 34 , 54 ]. Such combinations transcend mere summation, engendering amplifying circuits: lactate diminution facilitates deeper T-cell ingress and effector potency, while invigorated T cells liberate interferon-γ and allied factors that refine vascular architecture, mitigate hypoxia, and curtail lactate generation. A compelling case arises from uniting LDH inhibition with anti-PD-1 in lung carcinoma models, where LDH inhibition attenuates histone lactylation and a PD-L1-high epigenetic configuration, and PD-1 blockade revitalizes CD8⁺ T-cell activity, collectively dismantling immune tolerance [ 35 , 42 , 88 ]. Cellular immunotherapies stand to gain substantially from lactate modulation. Adoptively infused tumor-infiltrating lymphocytes, CAR T cells, T cell receptor-engineered cells, and natural killer cells frequently succumb in solid tumors due to lactic acidosis and substrate contention [ 11 , 45 ]. Tumor pH neutralization with bicarbonate, or pharmacologic adjustment using proton pump or carbonic anhydrase IX inhibitors, enhances infiltration, durability, and cytokine output of transferred T cells in murine melanoma [ 14 , 97 ]. Metabolic adjuncts like glycolysis suppressors or MCT antagonists extend CAR T longevity in spheroid and xenograft systems; for example, MCT1 inhibition allied with CAR T cells amplifies CAR T-cell access and tumor elimination [ 62 , 88 ]. Natural killer-based modalities, encompassing CAR-NK cells, prove particularly vulnerable to low pH and high lactate, and concomitant buffering, carbonic anhydrase IX blockade, or lactate cascade interference bolsters natural killer cytolysis and persistence, with lactylation inhibition further fortifying natural killer metabolic robustness [ 11 , 15 , 35 ]. Nascent clinical and associative evidence suggests that individuals exhibiting high circulating or tumoral lactate may derive outsized benefits from these pairings [ 18 , 71 ]. Crafting such immuno-metabolic protocols demands meticulous consideration of sequencing, cohort stratification, pharmacodynamic surveillance, and tolerability, yet mounting data affirm that lactate interdiction primes the terrain for checkpoint inhibitors and adoptive therapies alike. Key therapeutic strategies targeting the lactate–acidosis axis are summarized in Table 2 . Table 2. Therapeutic strategies targeting the lactate–acidosis axis to enhance antitumor immunity Strategy Primary target / node Representative agents / approaches Main antitumor & immunologic effects Key challenges / limitations Reference Inhibition of lactate production (glycolysis / LDH) LDHA / lactate generation LDH inhibition; oxamate-related approaches ↓ tumor lactate; improved intratumoral nutrient allocation; enhanced antitumor immunity; synergy with ICB in models Systemic metabolic effects; context dependence Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models [ 104 ]; Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model [ 105 ]. Blockade of lactate transport MCT1/MCT4 (and CD147 accessory node) MCT1 blockade (e.g., AZD3965); MCT4 blockade/silencing; CD147 targeting; MCT1 blockade in CAR-T settings Limits lactate export/acidification; increases immune infiltration; improves RT/ICB/CAR-T responses in models Effector T cells may also use lactate transport; toxicity/timing/selectivity Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport [ 90 ]; MCT4 blockade increases the efficacy of immune checkpoint blockade [ 92 ]; MCT4-dependent lactate secretion suppresses antitumor immunity in LKB1-deficient lung adenocarcinoma [ 64 ]; Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies [ 98 ]. Modulation / buffering of tumor acidosis Extracellular pH Oral bicarbonate; proton pump inhibitor (PPI) strategies; CAIX/pH regulation nodes ↑ tumor pH; reversal of TIL anergy; reduced metastasis; improved therapy responsiveness (context-dependent) Systemic alkalosis/electrolyte risk; GI toxicity; patient selection Bicarbonate increases tumor pH and inhibits spontaneous metastases [ 14 ]; Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes [ 106 ]; Intermittent high dose proton pump inhibitor enhances the antitumor effects of chemotherapy in metastatic breast cancer [ 95 ]; Hypoxia activates the capacity of tumor-associated carbonic anhydrase IX to acidify extracellular pH 26 . Engineering lactate-resilient immune cells T/NK metabolic rewiring (transport, pH tolerance, exhaustion programs) Targeting lactate-metabolism nodes (e.g., MCT11 in exhausted T cells); manufacturing preconditioning; CAR-T metabolic tuning Maintains cytotoxicity/cytokines in high-lactate/low-pH niches; improves persistence and efficacy in models Safety and manufacturing complexity; off-tumor metabolic risks Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism [ 45 ]; Inhibition of lactate transport by MCT-1 blockade improves chimeric antigen receptor T-cell therapy against B-cell malignancies [ 98 ]. Combination with ICB / ACT Metabolic–immune co-targeting LDH inhibition + anti–PD-1; MCT4 blockade + ICB; genotype-linked lactate export programs + ICB Converts glycolytic “cold” tumors toward inflamed phenotypes; ↑ CD8 infiltration; ↓ suppressor cells; improved response durability in models Optimal sequencing/dose unknown; overlapping toxicities; needs PD monitoring Inhibition of LDH-A by Oxamate Enhances the Efficacy of Anti-PD-1 Treatment in an NSCLC Humanized Mouse Model [ 105 ]; MCT4 blockade increases the efficacy of immune checkpoint blockade [ 92 ]. Biomarkers & imaging Lactate flux / pH / glycolysis surrogates Serum LDH (clinical correlate); FDG-PET correlates; hyperpolarized ¹³C-pyruvate MRI; pH imaging (pHLIP PET) Patient stratification and non-invasive monitoring of metabolism/pH and response Standardization/cost/availability; prospective validation Outcome of melanoma patients with elevated LDH treated with first-line targeted therapy or PD-1-based immune checkpoint inhibition [ 107 ]; Biologic correlates of (18)fluorodeoxyglucose uptake in human breast cancer measured by positron emission tomography [ 108 ]; Metabolic imaging of patients with prostate cancer using hyperpolarized [1-¹³C]pyruvate [ 109 ]; PET Imaging of Extracellular pH in Tumors with (64)Cu- and (18)F-Labeled pHLIP Peptides: A Structure-Activity Optimization Study [ 110 ]. Open in a new tab Note: LDH/LDHA, lactate dehydrogenase (A subunit); PDK, pyruvate dehydrogenase kinase; DCA, dichloroacetate; MCT, monocarboxylate transporter; CAIX, carbonic anhydrase IX; PPI, proton pump inhibitor; ICB, immune checkpoint blockade; ACT, adoptive cell therapy; CAR-T, chimeric antigen receptor T cell; FDG-PET, 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography; hyperpolarized ¹³C MRI, hyperpolarized carbon-13 magnetic resonance imaging. “Reference (Title)” includes only primary/original research articles (preclinical or clinical) demonstrating the strategy’s impact on lactate/acidosis and/or antitumor immunity; review articles were excluded Lactate-related biomarkers and clinical translation Lactate-associated transcriptional and metabolic signatures as prognostic and predictive tools Given the pivotal role of lactate in influencing tumor progression, lactate-associated biomarkers predictably hold prognostic significance. Elevated intratumoral lactate levels consistently associate with aggressive phenotypes and diminished survival, as evidenced by direct assays in diverse solid tumors that align with metastatic potential and clinical outcomes [ 3 – 5 ]. Since routine quantification of tissue lactate proves challenging, gene expression and metabolic profiles are under development as proxies for lactate-enriched, immunosuppressive microenvironments [ 111 , 112 ]. Signatures related to lactate metabolism commonly encompass glycolytic enzymes, transporters like MCT4, and hypoxia-responsive genes. In breast, lung, head-and-neck, and additional tumor types, elevated lactate scores delineate cohorts with inferior prognosis and correspond to hypoxic, immune-desert landscapes [ 111 – 113 ]. In melanoma, urothelial cancer, and triple-negative breast cancer, glycolytic or lactate-sensitive signatures further forecast responses to checkpoint inhibitors: neoplasms exhibiting low lactate-related gene expression more frequently benefit from PD-1/PD-L1 blockade, while high-lactate profiles signify resistance to immunotherapy [ 114 , 115 ]. Integration of these metabolic metrics into clinical decision frameworks could optimize patient stratification and study protocols. Serum lactate dehydrogenase functions as a straightforward circulating indicator of tumor metabolic intensity and load. Increased serum LDH constitutes a well-recognized unfavorable prognostic element in melanoma, lymphoma, and renal cell carcinoma, with associations to suboptimal checkpoint blockade responses [ 71 , 116 ]. Despite its lack of specificity, sustained LDH elevation or altered lactate metabolism may signify profoundly glycolytic pathology and contribute to prognostic modeling [ 3 , 117 ]. Metabolomic and lactylation-based signatures are advancing to delineate lactate-mediated epigenetic reprogramming and immune exclusion. Reliable lactate-centric biomarkers will prove essential for pinpointing individuals poised to gain from complementary metabolic interventions and for evaluating pharmacodynamic effects of lactate-directed treatments, such as through serial assessments of lactate gene indices or serum LDH. Non-invasive assessment of lactate and pH in patients Non-invasive modalities for measuring tumor lactate and acidity are indispensable for advancing lactate-focused therapies and biomarkers. Hyperpolarized ¹³C magnetic resonance imaging stands as a premier technique: administration of [1-¹³C]pyruvate permits dynamic monitoring of its transformation to lactate, highlighting zones of intensified glycolytic activity that correlate with malignancy in prostate, brain, and other cancers [ 118 – 120 ]. In glioblastoma, this method delineates intratumoral variability and oxygen-deprived, lactate-laden regions, with reductions in lactate signal post-radiation or molecular therapy serving as prompt indicators of response [ 121 , 122 ]. Analogously, hyperpolarized ¹³C-bicarbonate imaging derives extracellular pH from bicarbonate-CO₂ equilibria and has delineated acidic compartments in human metastatic lesions, providing a means to track tumor acidosis and its therapeutic alteration [ 123 , 124 ]. Positron emission tomography augments these strategies. Although FDG-PET lacks lactate specificity, it pinpoints glycolytic foci prone to lactate accumulation [ 125 ]. Novel tracers broaden this utility: pH-responsive agents like ⁶⁴Cu-conjugated pH-low insertion peptides concentrate in acidified niches [ 110 ], whereas investigational ¹¹C- or ¹⁸F-lactate derivatives and MCT1-directed probes such as [¹⁸F]DASA-23 seek to image lactate shuttling and efflux [ 126 ]. Standard and refined magnetic resonance spectroscopy identifies lactate signals, especially in cerebral neoplasms, albeit constrained by detection thresholds and spatial precision [ 127 , 128 ]. Circulating and tissue-derived biomarkers afford supplementary insights into tumor metabolism. Serum LDH, and in specific contexts, lactate or bicarbonate concentrations mirror overall metabolic strain and act as rudimentary stand-ins for tumor glycolysis and buffer therapy oversight [ 129 ]. Exosomes shed by tumors bearing LDH, CAIX, or related metabolic effectors, alongside metabolomic analyses of biopsies, cyst aspirates, or needle samples, enable targeted evaluation of lactate pathways [ 130 ]. Practically, FDG-PET paired with serum LDH will likely steer initial patient triage, while hyperpolarized ¹³C imaging and metabolomics progressively bolster pharmacodynamic evaluation [ 131 , 132 ]. Collectively, these maturing imaging and biomarker modalities will facilitate classification of patients harboring metabolically immunosuppressive tumors and enable contemporaneous oversight of interventions modulating tumor lactate and acidosis. Outstanding challenges and future directions Limitations of current experimental models and methodological gaps Current insights into lactate’s role in cancer are constrained by limitations in experimental systems and analytical approaches. Conventional two-dimensional cultures subject tumor cells to homogeneous oxygen and nutrient conditions, failing to capture the hypoxic gradients, acidosis, spatial diversity, and intricate immune dynamics characteristic of human neoplasms [ 3 , 23 ]. Transplantable murine tumors in young, inbred hosts frequently display exaggerated metabolic profiles that diverge from the gradual progression of human malignancies [ 8 ], while interspecies variations in immune metabolism may misrepresent lactate’s influence on T-cell responses [ 11 ]. Moreover, real-time assessment of lactate concentrations, pH fluctuations, and histone lactylation in vivo remains elusive; most techniques depend on terminal tissue harvesting, yielding static snapshots rather than dynamic or single-cell resolution data [ 3 , 35 , 45 ]. Although co-culture, organoid, and organotypic platforms represent advances, they often fail to fully incorporate viable immune elements, vascular networks, or authentic physiological gradients [ 23 , 64 ]. Clinical investigations of immune metabolism are similarly limited, with scant longitudinal cohorts that merge sequential biopsies, sophisticated imaging, and comprehensive metabolic analyses. Tools for locus-specific quantification of histone lactylation are in their infancy, hindering detailed mechanistic studies and compound screening. Overcoming these deficiencies demands the adoption of multicellular three-dimensional constructs, such as tumor-on-chip devices that integrate immune infiltrates and fluidic perfusion, alongside enhanced biosensors and imaging modalities for cellular-level lactate and pH tracking, and computational models to predict metabolite dynamics. More representative preclinical paradigms, including genetically engineered mice harboring spontaneous tumors in immunocompetent backgrounds, will prove indispensable for evaluating lactate-directed therapies with genuine translational potential. Balancing tumor targeting with preservation of systemic and immune-cell metabolism A core hurdle in developing lactate-targeted therapies lies in attaining tumor specificity while safeguarding host and immune metabolic integrity. Lactate constitutes a fundamental metabolite essential for physiological processes including muscle performance during exertion, red blood cell function, kidney metabolism, neural energetics, and immune activation [ 48 , 133 , 134 ]; indiscriminate systemic disruption of lactate synthesis or shuttling carries substantial risks of off-target adverse effects. Normal tissues with high glycolytic demands, particularly skeletal muscle under stress, rely on MCT1-facilitated lactate exchange [ 135 ]. Widespread MCT1 inhibition might impede lactate clearance, precipitating fatigue, muscle pain, or paradoxical acidosis [ 136 ]. Initial trials with the MCT1 antagonist AZD3965 have identified tolerable on-target sequelae, such as compromised exercise capacity, without severe muscular or cardiac compromise; however, expanded cohorts are needed to uncover nuanced toxicities [ 91 , 137 ]. Immune populations present additional complexities. Effector T cells engage aerobic glycolysis to sustain proliferation and cytokine synthesis; systemic interference with glycolysis or LDH could attenuate antitumor immunity [ 11 , 47 ]. Dichloroacetate, despite reducing tumor lactate, has been observed to redirect human CD4⁺ T cells toward regulatory, IL-10-dominant profiles, and LDHA ablation in murine T cells curtails cytokine release [ 11 , 83 ]. These findings advocate for tumor-preferential tactics, including nanoparticle-mediated LDH inhibitor administration that capitalizes on enhanced tumor permeability, isoform-selective targeting enriched in neoplasms, or temporally restricted regimens administered during phases of reduced effector T-cell metabolic demand [ 138 , 139 ]. MCT inhibitors exemplify the need for calibrated dosing and precision. Inhibition of MCT1/2 can sequester lactate within T cells, inducing intracellular acid overload and impaired expansion, yet IL-2 output remains intact [ 45 , 98 ]. Regulatory T cells exhibit greater reliance on MCT1 for lactate import compared to conventional T cells, affording a selectivity margin wherein partial or localized MCT1 blockade disproportionately impairs regulatory T cells without wholly compromising effectors [ 34 , 54 ]. Therapies modulating systemic bicarbonate and pH must adhere to stringent physiological boundaries. Overzealous bicarbonate administration risks metabolic alkalosis, especially in renal-impaired patients, necessitating rigorous patient screening, electrolyte and arterial blood gas oversight, and incremental dosing [ 140 , 141 ]. Preliminary applications of oral bicarbonate in advanced malignancies have demonstrated feasibility but underscored the imperative for vigilant monitoring [ 14 ]. Prolonged metabolic perturbation evokes concerns regarding neurotoxicity, immune polarization shifts, or adaptive tumor reliance on substitute substrates, potentially exacerbating systemic issues like cachexia [ 142 ]. Regional or intermittent protocols, such as intralesional depots, catheter-delivered buffering, or neoplasm-directed lactate oxidase gene transfer with concomitant neutralization of reactive intermediates, provide avenues to localize benefits and curtail bystander harm [ 96 ]. In essence, an optimal equilibrium demands judicious dosing, precision delivery, continuous surveillance of immune metabolic strain, and flexible adjustments. Realizing this equilibrium will hinge on interdisciplinary synergy among oncologists, immunologists, and pharmacologists to harness tumor lactate dependency while upholding organismal metabolic equilibrium. Integrating lactate biology with broader metabolic and spatial multi-omics landscapes Lactate functions amid an intricate metabolic web within the tumor microenvironment, and maximizing its therapeutic utility necessitates a holistic perspective on tumor metabolism and architectural organization. Contemporary multi-omics technologies are pivotal to this endeavor. Metabolomics delineates the array and concentrations of metabolites including lactate, adenosine, and kynurenine; single-cell and aggregate transcriptomics elucidate cellular responses to these signals, encompassing lactate transporter and hypoxia-inducible gene expression; spatial transcriptomics and proteomics delineate the topographic distribution of metabolic and immune phenotypes across tumor structures [ 3 , 7 , 23 ]. Fusing these modalities can yield metabolic cartographies that superimpose lactate distribution onto immune cell positioning. Such representations may clarify why regulatory T cells and exhausted T cells aggregate in oxygen-deprived, perinecrotic, lactate-saturated zones, whereas viable CD8⁺ T cells localize to vascular-proximal areas [ 143 , 144 ]. They can also identify chemokines, cytokines, and stromal elements sustaining these compartments, informing combinatorial regimens like lactate attenuation coupled with blockade of regulatory T cell-recruiting signals [ 145 ]. Lactate must be contextualized alongside concurrent metabolic regulators. Pathways involving adenosine, kynurenine, glutamine, and fatty acids intersect with hypoxia and glycolysis [ 7 ]. Multi-omics integration can ascertain whether lactate-dense regions coincide with elevated adenosine synthesis, IDO-mediated kynurenine production, or compensatory glutaminolysis and lipid catabolism, thereby proposing synergistic interventions addressing lactate and these allied pathways [ 7 , 23 ]. Sequential profiling pre-, intra-, and post-treatment can illuminate adaptive metabolic shifts under therapeutic selective pressure, unmasking nascent resistance mechanisms [ 114 ]. At the epigenetic level, lactate-induced histone lactylation presumably interacts or contends with acetylation and methylation at critical immune-regulatory sites [ 35 , 37 ]. Consolidated chromatin analyses during lactate perturbation can evaluate whether resistance-associated genes, such as those governing immune checkpoints, rely on lactylation [ 34 , 46 ]. Ultimately, computational simulations and machine learning will be vital to distill these multifaceted datasets into predictive models of prognosis and therapeutic susceptibility. Within this paradigm, lactate emerges not as an isolated entity but as an interconnected component in a comprehensive immunometabolic framework, facilitating tailored combinatorial designs and spatially guided therapies. Key unanswered questions and priorities for translational research Unresolved queries will define the trajectory of lactate investigations in the ensuing decade. A primary imperative is to delineate the contributions of the lactate anion from those of acidity [ 10 ]. Since lactic acid generation inextricably links lactate and protons, the relative attribution of immune dampening to pH versus lactate-specific transduction and lactylation remains ambiguous [ 11 , 54 ]. Does pH neutralization suffice to revive T-cell efficacy, or do GPR81-mediated signals and lactylation persist? Reciprocally, does interception of lactate receptors or transporters adequately counteract suppression amid ongoing acidosis? Resolving these distinctions will guide whether interventions should emphasize pH equilibration, lactate signaling disruption, or concurrent approaches. Lactate’s immunological consequences exhibit marked contextual variability. As detailed in Sect. 3 , its overarching influence on immunity fluctuates with microenvironmental and temporal factors. Dosage, duration, and cellular maturation stage presumably govern whether lactate acts as an energy source or inhibitor [ 146 , 147 ]. Modest or fleeting exposure may promote T-cell stemness, implying that subdued lactate levels sustain oxidative, memory-oriented states, whereas intense, sustained concentrations provoke exhaustion [ 45 , 46 ]. This duality suggests that brief lactate exposure could prove advantageous in enhancing T cell stemness for adoptive therapies, despite chronic exposure’s deleterious effects. A further critical inquiry concerns the premier therapeutic locus within the lactate cascade: glycolytic catalysts, LDH, MCTs, GPCRs like GPR81 and GPR65, or lactylation effectors. Head-to-head evaluations are essential to weigh potency against adverse profiles and pathway redundancy. Selective antagonism of lactate receptors or lactylation enzymes in immune or stromal subsets might reconfigure the microenvironment with diminished organismal repercussions compared to sweeping glycolysis or transport blockade [ 11 , 42 , 54 ]. Concurrent efforts must chart adaptive evasions, encompassing upregulation of adenosine or alternate substrates like glutamine and fatty acids. Lactate’s interactions with contemporary immunotherapies—including vaccines, oncolytic agents, and TGF-β inhibitors—warrant exploration, as do synthetic biology paradigms that harness lactate as an activator for engineered cellular responses. Another focal area involves establishing clinical surrogates and indicators: which imaging, metabolic, and immunologic metrics optimally reflect lactate pathway engagement, and which preliminary alterations can proxy for efficacy when overt regression lags? The mechanisms of histone and protein lactylation in immune populations are nascently understood [ 35 , 37 ]. Cataloging lactylated transcription factors, elucidating lactylation’s convergence with exhaustion cascades, and identifying selective modifiers will unveil novel epigenetic targets [ 35 ]. Likewise, probing lactate’s modulation of innate lymphoid cells—such as strategies to enhance their antitumor contributions—represents a burgeoning domain deserving intensified scrutiny [ 49 ]. In aggregate, prospective inquiries must resolve mechanistic underpinnings and propel these discoveries toward clinical utility. Lactate’s position as an instigator of immune evasion is incontrovertible; the forthcoming era will ascertain the proficiency with which this comprehension can elevate cancer immunotherapy. Acknowledgements The authors acknowledge the use of AI-assisted generation technologies for English language polishing and for the initial drafting of schematic sketches/figures. All AI-assisted outputs were reviewed, verified, and substantially edited by the authors, who take full responsibility for the final content. Author contributions XW and QW conceived the topic and designed the overall structure of the review. XW, DX, and SC conducted the literature search and information collection. XW drafted the manuscript. DX, SC, BD, GD, and YH contributed to critical revision of the content, refinement of key concepts, and improvement of figures/tables. QW provided supervision, coordinated revisions, and finalized the manuscript. All authors read and approved the final version. Funding Research and Application Demonstration of Key Technologies for Computing Power and Data Sharing Services in Large AI Models. Department of Science and Technology of Hunan Province. 2025JK2004. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. 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