REVIEW article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1468495
Tumor Microenvironment in Hepatocellular Carcinoma: A Comprehensive Review
Provisionally accepted
- 1Government College University, Faisalabad, Faisalabad, Pakistan
- 2National Institute for Biotechnology and Genetic Engineering (Pakistan), Faisalabad, Punjab, Pakistan
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Hepatocellular carcinoma (HCC), the most common primary liver cancer, arises predominantly from hepatocytes, and is a leading cause of cancer-related deaths globally. Its pathogenesis is initiated by different etiologies, including chronic viral infections, metabolic dysfunction-associated steatotic liver disease, alcohol-induced steatohepatitis, and aflatoxin exposure, which collectively promote hepatocarcinogenesis through persistent inflammation, fibrosis, and immune dysregulation. The tumor microenvironment of HCC is characterized by a dynamic interaction of immunosuppressive cells such as regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and dysfunctional effector cells, including exhausted CD8 + T cells and impaired natural killer cells. These interactions stimulate immune evasion by upregulated checkpoint molecules (PD-1, CTLA-4, TIGIT), inhibitory cytokines (IL-10, TGF-β), and aberrant signaling pathways (WNT/β-catenin, MYC, TP53). Emerging immunotherapies, particularly immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 and CTLA-4, have revolutionized HCC treatment. Combinatorial strategies by using ICIs with tyrosine kinase inhibitors, anti-angiogenics, or locoregional therapies show potential in overcoming immunosuppression and improving survival. This review aims to explain the immunological and metabolic mechanisms highlighting HCC progression, explores advances in therapeutic interventions, and ongoing clinical trials aimed at optimizing outcomes for HCC patients.
Keywords: Hepatocellular Carcinoma, Immune landscape, immune cells, Tumor Microenvironment, immune checkpoint inhibitors, curative strategies
Received: 22 Jul 2024; Accepted: 16 May 2025.
Copyright: © 2025 Zarlashat, Mushtaq and Ghaffar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yusra Zarlashat, Government College University, Faisalabad, Faisalabad, Pakistan
Abdul Ghaffar, Government College University, Faisalabad, Faisalabad, Pakistan
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