Chemotherapy-induced macrophage CXCL7 expression drives tumor chemoresistance via the STAT1/PHGDH-serine metabolism axis and SAM paracrine feedback to M2 polarization

• DOI: 10.1038/s41419-025-07712-y
• Publication Date: 2025-05-14T19:15:47Z
• Authors: Shuguang Liu; Hui Gong; Peihang Li; Jiahao Hu; Yixuan Li; Rou Xu; Junchao Cai; Shuqi Wang; Jiayi Cai; Hongmei Ma; Xirong Mi; Yifan Li; Qingbo Zhou; Qiming Zhou; Weiqiang Yang; Riqing Li; Libing Song; Lishan Fang

Abstract Chemotherapy resistance in colorectal cancer (CRC) remains a major obstacle clinical oncology. Analysis of specimens from chemotherapy-resistant patients revealed elevated CXCL7 expression tumor-associated macrophages (TAMs). Through integrated vitro and vivo studies, we demonstrated that chemotherapy induces tumor cell-macrophage crosstalk, leading to upregulation TAMs. Using co-culture system, observed CXCL7+ confer chemoresistance CRC cells. Mechanistic investigations activates the CXCR2 receptor on cells, triggering interferon signaling promoting serine metabolism through STAT1-dependent transcriptional phosphoglycerate dehydrogenase (PHGDH), key enzyme biosynthesis. This metabolic reprogramming enhances paracrine secretion S-adenosyl methionine (SAM), which drives resistance. Furthermore, CXCL7-mediated SAM turn promotes M2 macrophage polarization sustains Our findings reveal CXCL7-SAM feedback loop between cells establishes chemoresistant niche. interaction represents promising therapeutic target for overcoming CRC.