Revisiting the immunosuppressive microenvironment in hepatocellular carcinoma: a functional taxonomy of immune cells and therapeutic targeting.
TL;DR
This review provides an integrated and conceptual analysis of the HCC immune landscape, delineating the mechanistic drivers underlying immune suppression, summarizes current immune-based classification frameworks, and dissects the context-dependent functions of key immune cell populations in tumor progression.
Abstract
Despite transformative success in other solid tumors, immunotherapy has encountered a formidable barrier in hepatocellular carcinoma (HCC), a profoundly immunosuppressive tumor microenvironment (TME) that is predominantly "cold" and also exhibits remarkable heterogeneity across patients. This inter-patient variability in the immune context leads to different responses to treatment, limits clinical efficacy, and highlights the critical need for a deeper, systems-level understanding of the HCC immune landscape. This review provides an integrated and conceptual analysis of the HCC immune landscape. It delineates the mechanistic drivers underlying immune suppression, summarizes current immune-based classification frameworks, and dissects the context-dependent functions of key immune cell populations in tumor progression. Furthermore, this review surveys established TME-targeting therapies comprising primarily immune checkpoint blockade strategies and their clinically validated combinations, and highlights emerging agents and concepts under preclinical and early clinical development. By integrating mechanistic insights with immune classification and therapeutic advances, this review aims to provide a unifying framework to inform the rational design of next-generation immunotherapies for HCC.