Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance

TL;DR

This paper explores how mitochondrial dysfunction in liver cancer affects immune responses and treatment resistance, suggesting new strategies to improve immunotherapy.

Contribution

The paper integrates mitochondrial metabolism and immune escape mechanisms to propose novel combination therapies for HCC.

Findings

Mitochondrial dysfunction in HCC supports tumor survival and immune evasion.

Metabolic reprogramming in HCC reduces T-cell function and promotes exhaustion.

Targeting mitochondrial pathways may enhance immunotherapy responses in HCC.

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.

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