CAP1-Mediated m6A modification of RRM2 suppresses tumor-associated M2 macrophage polarization and colorectal cancer growth.

Colorectal cancer (CRC) progression is critically regulated by dynamic interactions between tumor cells and tumor-associated macrophages (TAMs), which shape the immuno-suppressive tumor microenvironment. In this study, we identify CAP1 as a novel regulator of this crosstalk through its control of RNA methylation-dependent M2 macrophage polarization. Clinical analysis reveals significant CAP1 downregulation in CRC tissues compared to adjacent normal mucosa, with its expression positively correlating with patient survival outcomes. While CAP1 knockdown did not show cell-autonomous effects on CRC proliferation in vitro, it dramatically enhanced tumor growth in immuno-competent mouse models. Further mechanistic studies uncover that CAP1 deficiency in tumor cells triggers a ALKBH5-mediated increase in m⁶A RNA methylation, specifically enhancing the translation and secretion of RRM2. This tumor-derived RRM2 potently drives M2 polarization of TAMs, creating a pro-tumorigenic niche that facilitated the proliferation of CRC cells in turn. Moreover, the RRM2 inhibitor shows considerable efficacy in treating tumors with low expression of CAP1. Collectively, this study provides new insights into how tumor cells regulate immune responses through post-transcriptional modification and suggests potential therapeutic strategies targeting the CAP1-RRM2 axis in CAP1-deficient CRCs.