Metabolic regulation of immunity in the tumor microenvironment.

Metabolic-immune crosstalk in the tumor microenvironment (TME) is a critical driver of tumorigenesis, progression, and immune evasion. Tumor cells undergo profound metabolic reprogramming, causing nutrient competition, toxic metabolite accumulation, and the formation of cold niches that gradually exhaust effector immune cells. In contrast, immunosuppressive cells exhibit strong metabolic adaptability, reinforcing the suppressive milieu. Moreover, tertiary lymphoid structures provide nutrient- and oxygen-rich "moats" that sustain the functions of B and T cells. In addition, metabolic-immune interactions establish novel checkpoints through an "enzyme-metabolite-receptor" axis, which synergize with PD-1/CTLA-4 pathways to promote resistance to immune checkpoint inhibitors (ICIs). Although monotherapies with metabolic inhibitors have shown limited efficacy, their combination with ICIs is promising. Therefore, this review discusses the field from three perspectives: metabolic stress in the TME, immune cell adaptation, and targeting metabolic immune checkpoints in combination with immunotherapy.