Drug resistance mechanisms of immunotherapy and translational strategies for reversing resistance for hepatocellular carcinoma: from bench to bedside

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and remains a major therapeutic challenge. In recent years, immune checkpoint inhibitors (ICIs), represented by PD-1/PD-L1 and CTLA-4 inhibitors, have revolutionized the field of HCC treatment and become the cornerstone of standard immunotherapy regimens, drastically altering the treatment landscape for advanced and unresectable HCC. However, primary and/or acquired drug resistance remains the leading cause of treatment failure, severely limiting the long-term clinical benefits of immunotherapy for HCC patients. This review aims to systematically summarize current research on immunotherapy for HCC, with a focus on drug resistance mechanisms across multiple dimensions: immunosuppressive tumor microenvironment, intrinsic tumor cell factors, and systemic and environmental influences. Potential strategies to overcome resistance are discussed, such as rational combination therapy with antiangiogenic or targeted agents, novel immune targets, nanotechnology-enabled precise delivery, and tumor organoid models for personalized treatment. Future advancements should focus on precision multimodal combinations, innovative therapeutic platforms, and individualized strategies guided by multi-omics and AI, aiming to overcome efficacy bottlenecks and improve patient survival.