Ivarmacitinib Combined With Camrelizumab and Apatinib for Unresectable Advanced Hepatocellular Carcinoma With Acquired Resistance to Immune Checkpoint Therapy: A Single-Arm Exploratory Clinical Study

Background： Hepatocellular carcinoma (HCC) stands as a formidable global health challenge. It ranks as the sixth most common malignant solid tumor worldwide and the third leading cause of cancer-related mortality. The disease is characterized by its insidious onset, rapid progression, and high recurrence rates, contributing to a dismal 5-year survival rate of approximately 18%. A critical factor in this poor prognosis is that nearly 57% of patients are diagnosed at an advanced stage, where curative surgical resection is no longer feasible. For these patients with unresectable advanced HCC (uHCC), effective systemic therapies are paramount to extend survival and improve quality of life. The advent of immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis, has revolutionized the treatment landscape for numerous advanced cancers, including uHCC. These agents work by blocking the inhibitory signals that tumor cells exploit to evade immune surveillance, thereby reactivating cytotoxic T cells to attack the cancer. However, the clinical benefit of ICI-based therapies is not universal. A substantial proportion of patients-estimated between 15% to 40%-derive limited or no benefit. Primary resistance is defined as a lack of initial response, while acquired resistance refers to disease progression after an initial period of clinical benefit. There is no established, evidence-based standard of therapy for uHCC patients who progress following first-line ICI combination therapy, highlighting an urgent need for novel therapeutic approaches. The mechanisms underlying acquired resistance to ICIs are multifaceted and intricately linked to dynamic remodeling of the tumor immune microenvironment (TME). Several key pathways contribute: 1. Loss of Tumor Immunogenicity: Immune editing during treatment can select for tumor cell clones with low neoantigen expression, making them less visible to the immune system. 2. Immune Suppressive Cell Infiltra