Hepatocellular carcinoma tumor immune microenvironment: heterogeneity and therapeutic strategies

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, with immunotherapy emerging as a pivotal strategy for advanced disease. However, treatment responses remain highly variable, largely due to the complex and dynamic tumor immune microenvironment (TIME). This review systematically examines the composition, heterogeneity, and function of the TIME of HCC, focusing on the interplay between immunosuppressive cells - such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) - and functional immune cells, including CTLs, NK cells, and DCs. We highlight the spatial and temporal heterogeneity of the TIME, shaped by underlying HCC etiologies, which critically influences immune evasion and therapeutic outcomes. We also evaluate current immunotherapeutic approaches, particularly immune checkpoint inhibitors (ICIs), adoptive cell therapies, and strategies targeting metabolic and microbial remodeling of the TIME. Finally, we discuss emerging combination therapies and future directions aimed at overcoming immunosuppressive barriers to enhance personalized treatment and improve clinical outcomes in HCC. A deeper understanding of TIME biology is essential for developing more effective immunotherapeutic strategies.

Keywords

Hepatocellular carcinoma / tumor immune microenvironment / heterogeneity / immunotherapy / immune checkpoint inhibitors

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