Immunometabolism of tumor-associated macrophages in driving colorectal cancer.

Colorectal cancer (CRC) remains a leading cause of cancer mortality. Tumor-associated macrophages (TAMs) regulate CRC progression through functional polarization and metabolic reprogramming. Beyond the classical M1/M2 paradigm, single-cell and spatial studies reveal heterogeneous TAM subsets with distinct metabolic programs, spatial organization, and stage-dependent functions. This review delineates how TAM metabolic reprogramming drives CRC via metabolite-induced PD-L1 expression, oncogenic signaling, and crosstalk with chronic inflammation and gut microbiota. We emphasize spatial metabolic heterogeneity, TAM-tumor metabolic symbiosis, the stage-dependent duality of M2-like macrophages in colitis versus CRC, and pathogen-driven cross-kingdom manipulation. Clinical evidence linking TAM metabolic features to molecular subtypes, metastasis, prognosis, and treatment response is integrated, and methodological challenges in distinguishing true metabolic reprogramming from phenotypic changes are discussed. Therapeutic strategies targeting TAM metabolism, including small molecules, chemotherapeutics, TCM, nanomedicine, probiotics, and combinations, are summarized, offering precise TAM reprogramming to reverse immunosuppression and overcome CRC therapeutic bottlenecks.