The role of macrophages has transcended the traditional binary framework of M1/M2 polarization, emerging as "tissue microenvironment engineers" that dynamically govern organismal homeostasis and disease progression. Under physiological conditions, they maintain balance through phagocytic clearance, metabolic regulation (e.g., lipid and iron metabolism), and tissue-specific functions (such as hepatic detoxification by Kupffer cells and intestinal microbiota sensing), all meticulously orchestrated by epigenetic mechanisms and neuro-immune crosstalk. In pathological states, their functional aberrations precipitate chronic inflammation, fibrosis, metabolic disorders, and neurodegenerative diseases. Notably, this plasticity is most pronounced within the tumor microenvironment (TME): tumor-associated macrophages (TAMs) polarize toward a protumoral phenotype under conditions of low pH and high reactive oxygen species (ROS). They promote angiogenesis via vascular endothelial growth factor (VEGF), suppress immunity through interleukin-10 (IL-10)/programmed death-ligand 1 (PD-L1), and facilitate tumor invasion by degrading the extracellular matrix, ultimately fostering an immune-evasive niche. Novel intervention strategies targeting TAMs in the TME have shown remarkable efficacy: CRISPR-Cas9 spatiotemporal editing corrects aberrant gene expression; pH/ROS-responsive nanoparticles reprogram TAMs to an antitumoral phenotype; chimeric antigen receptor-macrophage (CAR-M) 2.0 enhances antitumor immunity through programmed death-1 (PD-1) blockade and IL-12 secretion; and microbial metabolites like butyrate induce polarization toward an antitumor phenotype. Despite persisting challenges-including the functional compensation mechanisms between tissue-resident and monocyte-derived macrophages, and obstacles to clinical translation-the macrophage-centered strategy of "microenvironmental regulation via cellular engineering" still holds revolutionary promise for the treatment of tumors and other diseases.
