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

  • Cell Death Dis. 2025 May 14;16(1):379. doi: 10.1038/s41419-025-07712-y.
Shuguang Liu  #  1 ,  Hui Gong  #  2 ,  Peihang Li  #  3 ,  Jiahao Hu  #  3 ,  Yixuan Li  3 ,  Rou Xu  3 ,  Junchao Cai  4 ,  Shuqi Wang  5 ,  Jiayi Cai  6 ,  Hongmei Ma  1 ,  Xirong Mi  7 ,  Yifan Li  2 ,  Qingbo Zhou  8 ,  Qiming Zhou  9 ,  Weiqiang Yang  10 ,  Riqing Li  11 ,  Libing Song  12 ,  Lishan Fang  13
Affiliations
  • 1. Department of pathology, The Eighth Affiliated Hospital, Sun Yat-Sun University, Shenzhen, China.
  • 2. Shenzhen Nanshan People's Hospital, Shenzhen, China.
  • 3. Medical Research Center, The Eighth Affiliated Hospital, Sun Yat-Sun University, Shenzhen, China.
  • 4. Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 5. Department of Microbiology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 6. Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
  • 7. Shenzhen University Medical School, Shenzhen, Guangdong, China.
  • 8. Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 9. Shenzhen Nanshan People's Hospital, Shenzhen, China. [email protected].
  • 10. Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, China. [email protected].
  • 11. Shenzhen Inspection and Testing Center of Agricultural Product Quality and Safety, Shenzhen, China. [email protected].
  • 12. Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 13. Medical Research Center, The Eighth Affiliated Hospital, Sun Yat-Sun University, Shenzhen, China. [email protected].
  • # Contributed equally.
PMID: 40368902 DOI: 10.1038/s41419-025-07712-y
Abstract

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

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