Metabolic insights into TAMs and the tumor immune microenvironment: Regulatory mechanisms and therapeutic interventions

Tumor-associated macrophages (TAMs) are pivotal regulators of the tumor immune microenvironment exhibiting a dual role in tumor therapy by functioning as both pro-tumorigenic effectors and anti-tumor agents. Tumor cells reprogram macrophages towards the pro-tumorigenic M2 phenotype through the induction of signaling molecules and manipulation of metabolic pathways. Recent evidence indicates that the interplay between TAM functional polarization and metabolic reprogramming profoundly influences anti-tumor immunity across multiple dimensions. TAMs, in turn, collectively modulate the immunosuppressive niche via a complex interaction network involving dynamic metabolite exchange, immune checkpoint signaling, and sensing of the physical microenvironment. In this review, we integrate current understanding of TAM metabolic networks, elucidate key mechanisms by which they remodel the immunosuppressive microenvironment through metabolic crosstalk, and outline emerging therapeutic strategies targeting TAMs to overcome current treatment limitations.