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<p>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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月14日

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  • 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

摘要

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.