M2 macrophage associated genes shape prognosis and tumor progression in human colorectal cancer

Tumor-associated macrophages (TAMs) are key components of the colorectal cancer (CRC) microenvironment, yet the transcriptional programs associated with M2 states and their prognostic relevance remain incompletely defined. Here, single-cell RNA-seq analysis of CRC identified macrophages that were further classified into M0-like, M1-like, and M2-like states. Pseudotime analysis identified 311 genes associated with M2-like polarization. Cox and LASSO analyses yielded 16 M2-associated prognostic genes (M2Gs), whose robustness was further validated in an independent dataset. PLTP, NPL, and DCTPP1 were enriched in M2 macrophages in CRC tissues. Knockdown of these genes reduced IL-10-induced M2-like polarization, and conditioned media from knockdown macrophages suppressed the malignant phenotypes of HCT116 cells. Finally, a 16-M2G-based risk model stratified prognosis in TCGA and two independent cohorts. Collectively, our study defines an M2-like TAM-associated transcriptional signature with prognostic relevance in CRC and provides functional evidence that selected M2G modulate macrophage polarization and tumor cell phenotypes.