Resistance to immune checkpoint inhibitors in hepatocellular carcinoma: mechanisms and combination strategies to overcome it

Hepatocellular carcinoma (HCC) is predominantly diagnosed at an advanced stage and ranks as the third leading cause of cancer-related mortality worldwide. In recent years, the advent and clinical application of immune checkpoint inhibitors (ICIs) have markedly transformed the therapeutic landscape of HCC, yielding superior overall survival (OS) outcomes compared with conventional targeted therapies. Nevertheless, clinical benefit is limited to a subset of patients, largely due to drug resistance. Current evidence implicates both the tumor microenvironment and tumor cell-intrinsic factors as pivotal determinants of ICI resistance. Combination strategies have emerged as a central approach in HCC therapy, significantly enhancing the antitumor activity of ICIs. Notably, ICIs plus targeted therapy (anti-angiogenic agents), dual-ICI blockade, and ICI combined with locoregional therapy (transarterial chemoembolization) currently represent the most well-established and clinically validated approaches, being approved as first- or second-line treatments. In addition, complementary approaches, including traditional Chinese medicine and modulation of intestinal microbiota, demonstrate synergistic antitumor effects when integrated with ICI, representing promising avenues for further therapeutic optimization. This review mainly elucidates the underlying mechanisms of ICI resistance and examines both established and emerging combination strategies for HCC. Furthermore, it explores potential approaches to enhance the efficacy of ICI-based regimens, with the aim of improving long-term outcomes for patients with advanced HCC.