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Immune cell metabolic reprogramming mediates ICI therapy resistance

Zhi Xu1, Kequan Xu1, Yi Ju1

  • 1Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, PR China; Clinical Medicine Research Center for Minimally Invasive Procedure of Hepatobiliary & Pancreatic Diseases of Hubei Province, Wuhan 430071, PR China.

Trends in Cancer
|July 30, 2026
PubMed

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced malignancies; however, their efficacy in solid tumors remains limited by therapy resistance. This resistance arises from the metabolic reprogramming of immune cells in the tumor microenvironment (TME), a metabolic 'cage' where immune and cancer cells compete for nutrients. Immune effector cells succumb to metabolic exhaustion amid nutrient competition, whereas immunosuppressive cells augment inhibitory functions via metabolic adaptation, collectively mediating tumor immune evasion. This review systematically delineates the metabolic reprogramming features of immune cells in the TME, dissects the molecular mechanisms governing ICI resistance, and summarizes combination strategies targeting metabolic pathways to reverse resistance, providing theoretical and translational insights for optimizing cancer immunotherapy.

Keywords:
cancer therapeuticsimmune checkpoint inhibitorsmetabolic reprogrammingtumor microenvironment

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