Metabolic and epigenetic plasticity of tumor-associated macrophages shapes immunosuppressive outputs and immune checkpoint response.

Abstract

Immune checkpoint blockade (ICB) has transformed cancer therapy, but durable responses are frequently limited by tumor microenvironment-driven resistance. Tumor-associated macrophages (TAMs) are central mediators of this process because they sense metabolic stress and convert it into immunosuppressive programs that restrict antigen presentation, effector T cell entry, and cytotoxic function. This review conceptualizes the tumor microenvironment as a metabolic ecosystem shaped by hypoxia, lactate accumulation, acidosis, nutrient competition, lipid-rich niches, and amino-acid scarcity. We propose a context-dependent state-transition model in which these pressures are decoded by interconnected nutrient- and stress-sensing pathways, integrated through mitochondrial bioenergetic and redox adaptation, and translated by metabolite-dependent chromatin remodeling into persistent TAM functional programs that constrain the depth and durability of ICB responses. We further link glucose, lipid, and amino-acid metabolic circuitry to checkpoint resistance and propose therapeutic leverage tiers and biomarker layers for TAM metabolic reprogramming combined with ICB. This framework highlights actionable routes to overcome myeloid-driven immune resistance.