Metabolic reprogramming of myeloid antigen-presenting cells in the tumor microenvironment: mechanisms of antigen presentation failure and therapeutic opportunities.

Abstract

Antigen-presenting cells (APCs) translate tumor-derived signals into adaptive immune responses, yet their function is shaped by the metabolically hostile tumor microenvironment (TME). Hypoxia, acidosis, nutrient scarcity, and immunoregulatory metabolite accumulation can reprogram myeloid APC metabolism, impair antigen processing and presentation, weaken costimulatory signaling and cytokine production, and compromise antitumor T cell responses. In this review, we examine how glucose, lipid, amino acid, and mitochondrial metabolic perturbations drive subset-specific remodeling of dendritic cells and tumor-associated macrophages. We emphasize mechanistic links between defined metabolic stressors, discrete antigen-presentation defects, and downstream immune consequences, while framing APC dysfunction as context-dependent adaptive remodeling rather than passive metabolic collapse. We also distinguish impaired lymph-node priming from maladaptive intratumoral restimulation and discuss therapeutic strategies that remodel the TME, recalibrate APC-intrinsic metabolism, enhance targeted delivery, and engineer APC-like cellular functions. Together, these insights position APC immunometabolism as a potentially actionable determinant of tumor immune escape and therapeutic responsiveness.