# T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy

## TL;DR

This review discusses how T cell exhaustion limits immunotherapy effectiveness in liver cancer and explores strategies to overcome it.

## Contribution

The paper provides a comprehensive overview of T cell exhaustion mechanisms and therapeutic strategies specific to hepatocellular carcinoma.

## Key findings

- T cell exhaustion in HCC is driven by epigenetic, metabolic, and immunosuppressive factors.
- Combination therapies targeting multiple exhaustion pathways show promise for improving immunotherapy outcomes.
- Immune checkpoint blockade and metabolic reprogramming are emerging strategies to reverse T cell dysfunction.

## Abstract

Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti‐tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy‐based approaches for liver cancer.