Chemotherapy-Induced Macrophage CXCL7 Expression Drives Tumor Chemoresistance via the STAT1/PHGDH-Serine Metabolism Axis and SAM Paracrine Feedback to M2 Polarization

Chemotherapy resistance in colorectal cancer (CRC) poses a significant therapeutic challenge. Our study uncovers a novel mechanism in which chemotherapy induces CXCL7 expression in tumor-associated macrophages (TAMs), contributing to chemoresistance. CXCL7 overexpression in CRC cells activates the CXCL7/CXCR2 axis, leading to increased serine metabolism and tumor cell resistance to chemotherapy through upregulation of phosphoglycerate dehydrogenase (PHGDH). Furthermore, our data reveal that CXCL7 activates the interferon signaling pathway, with the transcription factor STAT1 enhancing PHGDH transcription. Additionally, CXCL7-mediated serine metabolism boosts the synthesis and release of S-adenosyl methionine (SAM), a molecule that promotes M2 polarization and triggers a positive feedback loop of CXCL7 expression in TAMs, reinforcing chemoresistance. Our study highlights the CXCL7/CXCR2-STAT1-PHGDH axis and SAM-induced macrophage polarization as key drivers of CRC chemotherapy resistance, pointing to potential new therapeutic targets.