ObjectiveTo summarize the key roles of M2-tumor-associated macrophages (M2-TAMs) in the progression of colorectal cancer (CRC) through the regulation of signaling pathways, and to discuss corresponding potential intervention strategies. MethodBased on a systematic review of published literature, this article comprehensively analyzes the key roles of M2-TAMs in the signaling pathways governing CRC progression and summarizes the upstream pathways regulating M2-TAMs recruitment and polarization, as well as the core downstream effector networks driving their pro-tumorigenic functions. ResultsAmong the upstream pathways of M2-TAMs, cytokine/chemokine pathways (CCL2/CCR2, CSF-1R, IL-6/JAK/STAT3, and CXCL12-CXCR4) mediate chemotactic recruitment and pro-tumor polarization, whereas metabolic sensing pathways (lactate and succinate) shape the pro-tumor phenotype of TAMs through metabolic reprogramming. The downstream effector pathways exhibit a clear functional division: the EGF/EGFR/PI3K/Akt/mTOR axis primarily mediates proliferation and survival, whereas the TGF-β/Smad/non-Smad, Wnt/β-catenin, and Notch/Jagged1 pathways synergistically drive invasion and metastasis. These pathways coordinately facilitate the pro-tumorigenic effects of M2-TAMs. Based on the above mechanisms, intervention strategies targeting key nodes such as CSF-1R, CCR2, and CXCR4 provide promising therapeutic options for CRC. ConclusionsThis review elucidates the key regulatory roles of M2-TAMs in CRC signaling networks. Based on these findings, multi-pathway combinatorial blockade and precise modulation of TAMs subpopulations deserve further investigation. However, TAMs plasticity, signal context-dependency, and microenvironment heterogeneity remain core bottlenecks limiting clinical translation. Future efforts should focus on the development of novel therapeutic modalities and the design and validation of combination regimens to promote the clinical translation of TAMs-targeted therapeutic strategies.
