The Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment and the Mechanism of Immune Therapy Resistance

Abstract

The efficacy of immune checkpoint inhibitors (ICIs) is often limited by primary and acquired resistance induced by the tumor microenvironment (TME), with the metabolic reprogramming of immune cells being the core mechanism. This review systematically analyzes the three key metabolic stresses in the TME: glucose deprivation, lactate accumulation, and adenosine accumulation. How these metabolic stresses, by reshaping the metabolic states and functions of T cells, macrophages, and dendritic cells, jointly construct an immunosuppressive ecosystem and lead to ICIs resistance. Glucose deprivation directly weakens the activation and function of effector T cells, while lactate and adenosine further inhibit effector immune cells and support the functions of immunosuppressive cells such as regulatory T cells and M2-type macrophages, ultimately forming a treatment-tolerant microenvironment. The article further explores therapeutic strategies targeting metabolic nodes such as lactate dehydrogenase A (LDHA), CD73/CD39 - adenosine axis, to reverse immunosuppression and enhance the efficacy of ICIs, and looks forward to the future direction of using "metabolism-immunity" typing to guide individualized combination therapy.