Next-generation therapies for hepatocellular carcinoma: CAR-T cell and anticancer peptide synergy.

Hepatocellular carcinoma (HCC), the most common primary liver cancer, is characterized by late diagnosis, limited treatment efficacy, and a highly immunosuppressive tumour microenvironment. Chronic liver injury, fibrosis, and inflammation are central to HCC pathogenesis, leading to genetic and epigenetic changes, particularly under oxidative stress from reactive oxygen species (ROS). Aberrant activation of pathways such as Wnt/β-catenin, contributes to uncontrolled proliferation, resistance to apoptosis, and metastasis. This review emphasizes how immunotherapy particularly immune checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cell therapy, has reshaped HCC treatment approaches. Advances in CAR-T designs targeting antigens like GPC3, AFP, and PD-L1, have been engineered to address antigen heterogeneity, T-cell exhaustion, and poor tumour infiltration. Mutant p53 and PD-L1 in the tumour microenvironment pose challenges to therapy by suppressing T-cell activity. Furthermore, anticancer peptides (ACPs), such as Tv1, SHLP6, R-Tf-D-LP4, and MOTS-c, exhibit selective cytotoxicity, mitochondrial targeting, and disruption of tumour-promoting pathways. Nanotherapeutics like PIR NPs, ThermoDox, and liposomal drug formulations improve drug stability, delivery, and specificity, providing controlled release and reduced toxicity. The integration of CAR-T therapy with ACPs, nanomedicine, and dual-checkpoint blockade such as tremelimumab-durvalumab, and nivolumab-ipilimumab demonstrate improved tumour regression and survival outcomes. Combination strategies that modulate ROS levels, inhibit angiogenesis, and utilize peptide-drug conjugates show promise in preclinical and early clinical studies. This review highlights the therapeutic synergy of next-generation peptide, cellular, and nanoplatform-based therapies in enhancing outcomes for advanced HCC.