Comprehensive review on immunotherapy for hepatocellular carcinoma: Current status and future perspectives.

Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, remains a major global health concern due to its high incidence and mortality rates. Although advances in surgery, chemotherapy, and radiotherapy have improved management, the prognosis for advanced-stage HCC remains poor. Immunotherapy has emerged as a transformative approach, aiming to harness and modulate the immune system to target malignant cells more effectively. This review provides an updated overview of immunotherapeutic strategies in HCC, highlighting key modalities such as immune checkpoint inhibitors (ICIs), neoantigen-based vaccines, and tumor mutational burden (TMB) as predictive biomarkers of treatment response. Particular attention is given to ICIs targeting PD-1/PD-L1 and CTLA-4 pathways, as well as novel immune targets under investigation to overcome therapeutic resistance. Despite encouraging clinical outcomes, significant challenges persist, including immune evasion mechanisms, limited response rates, treatment resistance, and the complexity of the immunosuppressive tumor microenvironment. Addressing these obstacles requires integrating genomic insights, artificial intelligence-driven biomarker discovery, and rational combinatorial strategies that pair ICIs with targeted agents, chemotherapy, or radiotherapy to enhance immune activation. Future directions emphasize the development of precision immunotherapy guided by molecular profiling and predictive biomarkers to improve patient stratification and treatment efficacy. This review consolidates current progress, identifies key limitations, and outlines emerging avenues to optimize the future landscape of HCC immunotherapy.