Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy

Abstract

Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of “metabolic siege” on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites-such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids-function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the “metabolism-epigenetics-immunity” axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.