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) 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.
Authors
- Riqing Li (ORCID: https://orcid.org/0000-0003-4397-2056)
- Weiqiang Yang
- Xiangbin Mi (ORCID: https://orcid.org/0000-0003-0698-6088)
- Peihang Li (ORCID: https://orcid.org/0009-0008-4698-921X)
- Jiahao Hu (ORCID: https://orcid.org/0009-0009-0361-9486)
- Qingbo Zhou (ORCID: https://orcid.org/0000-0003-2561-4917)
- Lishan Fang (ORCID: https://orcid.org/0000-0002-0183-861X)
- Ruliang Xu (ORCID: https://orcid.org/0000-0002-9165-4610)
- Libing Song (ORCID: https://orcid.org/0000-0002-5315-771X)
- Junchao Cai (ORCID: https://orcid.org/0000-0001-8412-6177)
- Shuguang Liu (ORCID: https://orcid.org/0000-0003-3564-8336)
- Yifan Li (ORCID: https://orcid.org/0000-0002-3895-1974)
- Shuqi Wang (ORCID: https://orcid.org/0000-0002-4460-7221)
- Yixuan Li (ORCID: https://orcid.org/0000-0002-8000-3417)
- Hongmei Ma (ORCID: https://orcid.org/0000-0001-5887-8850)
- Jiayi Cai (ORCID: https://orcid.org/0000-0002-1609-879X)
- Qiming Zhou (ORCID: https://orcid.org/0000-0002-6539-8043)
- Hui Gong (ORCID: https://orcid.org/0000-0003-3707-8429)
Institutions
- Sun Yat-sen University (CN)
- Shenzhen University (CN)
- Shenzhen Sixth People's Hospital (CN)
- ShenZhen People’s Hospital (CN)
- Peking University Shenzhen Hospital (CN)
- Shenzhen University Health Science Center (CN)
- Sun Yat-sen University Cancer Center (CN)
- Shenzhen Academy of Metrology and Quality Inspection (CN)
- Eighth Affiliated Hospital of Sun Yat-sen University
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-05-14
- DOI
- https://doi.org/10.1038/s41419-025-07712-y
- Citations
- 10
- Primary Topic
- Immune cells in cancer
- Type
- article
- Field-Weighted Citation Impact
- 7.97
Funders
- National Natural Science Foundation of China
- Sun Yat-sen University
- Huazhong University of Science and Technology
- National Key Research and Development Program of China
- Basic and Applied Basic Research Foundation of Guangdong Province