The epigenetic landscape of tumor-associated macrophages: orchestrating immune evasion in the tumor microenvironment

Abstract

Tumor-associated macrophages (TAMs), the predominant immune cell population within the tumor immune microenvironment (TIME), play a vital role in promoting immune evasion and driving tumor progression. Beyond their well-established roles in reprogramming oncogenic signaling and silencing tumor suppressors, emerging evidence highlights that epigenetic modifications also critically shape the immunogenic landscape of tumors by modulating the phenotype and function of infiltrating immune cells. The TIME imposes persistent metabolic and inflammatory stressors—such as hypoxia, nutrient deprivation, and lactate accumulation—that profoundly influence the epigenetic and transcriptional states of TAMs, promoting their phenotypic plasticity and skewing them toward immunosuppressive, pro-tumoral phenotypes. Notably, this dynamic and reversible reprogramming closely parallels the defining features of epigenetic regulation, which is inherently sensitive to environmental stimuli and governs cellular identity. In this review, we comprehensively examine how extracellular cues within the TME rewire the expression and activity of key epigenetic regulators in TAMs, activate downstream signaling pathways, and reshape their molecular functions to reinforce tumor-supportive programs. Deciphering these epigenetic circuits provides a framework for therapeutic strategies aimed at re-educating TAMs toward anti-tumor phenotypes and enhancing the efficacy of immunotherapies.