Advances in Tumor Microenvironment and Immunotherapeutic Strategies for Hepatocellular Carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy, largely driven by an immunosuppressive tumor microenvironment (TME) that facilitates tumor growth, immune escape, and resistance to therapy. Although immunotherapy-particularly immune checkpoint inhibitors (ICIs)-has transformed the therapeutic landscape by restoring T cell-mediated anti-tumor responses, their clinical benefit as monotherapy remains suboptimal. This limitation is primarily attributed to immunosuppressive components within the TME, including tumor-associated macrophages, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). To address these challenges, combination strategies have been explored, such as dual checkpoint blockade targeting programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), as well as synergistic use of ICIs with anti-angiogenic agents or TME-targeted interventions. These approaches have shown encouraging potential in enhancing immune efficacy. This review outlines the complex crosstalk between the TME and immunotherapeutic responses in HCC, emphasizing how combination regimens may overcome immune resistance. Furthermore, we discuss the remaining hurdles, including therapeutic resistance and immune-related adverse events, and propose future directions involving TME-associated biomarkers and individualized treatment strategies to improve patient outcomes.