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

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

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. zqm19771221@163.com.
  • 10 Department of Otolaryngology, Peking University Shenzhen Hospital, Shenzhen, China. 497450210@qq.com.
  • 11 Shenzhen Inspection and Testing Center of Agricultural Product Quality and Safety, Shenzhen, China. liriqing246@163.com.
  • 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. songlb@sysucc.org.cn.
  • 13 Medical Research Center, The Eighth Affiliated Hospital, Sun Yat-Sun University, Shenzhen, China. fanglsh5@mail.sysu.edu.cn.
  • # 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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