Tumor-driven metabolic reprogramming does not merely create a nutrient-deprived niche; it generates a network of aberrant metabolite signals that directly subvert antitumor immunity. Within the metabolically hostile tumor microenvironment (TME), specialized intracellular regulators-here defined as metabolic checkpoints-sense and integrate cues such as nutrient availability and metabolite accumulation. Unlike classical metabolic enzymes, these checkpoints act as decision-making hubs that (i) integrate multiple metabolic inputs, (ii) transduce them into specific intracellular signals, and (iii) dictate immune cell fate decisions, thereby orchestrating immune suppression and therapy resistance. Even successful immune checkpoint inhibitors (ICIs) face resistance driven by TME metabolic barriers, making metabolic checkpoints attractive therapeutic nodes. Recent advances highlight metabolic checkpoint intervention as a promising strategy to enhance immunotherapy responsiveness. This review dissects how metabolic checkpoints rewire three core signaling axes in immune cells: metabolite-driven epigenetic reprogramming, kinase/phosphatase modulation, and transcription factor control. We further clarify conceptual ambiguities distinguishing canonical from emerging regulators and explore their impact on immune modulation and resistance mechanisms. Finally, we propose a clinical translation roadmap that links specific metabolic checkpoint signatures to patient stratification, combination trial design, and mitigation of metabolic plasticity-driven resistance, moving beyond descriptive categorization toward actionable frameworks.
