New perspectives in immunotherapy for hepatocellular carcinoma: Focusing on resistance mechanism, biomarker, and personalized treatment.

The management of hepatocellular carcinoma (HCC) faces substantial and evolving challenges, driven by its aggressive biology, drug resistance, and the clinical urgency to detect recurrence. The treatment paradigm has undergone a profound transformation, evolving from surgical interventions and molecular targeted agents to the current era dominated by immunotherapy. Immune checkpoint inhibitors, particularly when used in combination with anti-angiogenic drugs or as part of dual-checkpoint blockade regimens, have established a new first-line standard of treatment for advanced HCC, delivering unprecedented survival improvements. Despite this progress, significant obstacles remain, including primary and acquired resistance, variable patient responses, and notably reduced efficacy in specific etiological subgroups. This comprehensive review synthesizes the emerging modalities such as bispecific antibodies, adoptive cell therapies, and innovative rational combinations that integrate systemic immunotherapy with locoregional treatments or novel targeted agents. Furthermore, we delve into the critical search for predictive biomarkers, encompassing liquid biopsy and multi-omics approaches, and dissect the complex cellular and molecular mechanisms underlying therapeutic resistance within the immunosuppressive tumor microenvironment. Finally, we outline future translational directions, emphasizing the expansion of immunotherapy, the development of tailored strategies for therapy-resistant disease, and the imperative move towards a personalized, biomarker-driven treatment framework. This review provides a cohesive overview of the field and charts a roadmap for future research to overcome the current challenges in HCC immunotherapy.