{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T04:52:28Z","timestamp":1791089548982,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82372961"],"award-info":[{"award-number":["82372961"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82372961"],"award-info":[{"award-number":["82372961"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Immune checkpoint blockade benefits only a minority of patients with triple-negative breast cancer (TNBC), and the tumour-intrinsic programmes that establish its immunosuppressive microenvironment remain poorly defined. Pyrimidine metabolism supplies nucleotides and one-carbon units in malignant cells, but whether it shapes the immune microenvironment is unknown. Integrating single-cell, bulk breast cancer transcriptomics with Xenium spatial transcriptomics, DTYMK knockdown, tumour-conditioned-medium co-culture and folate rescue, we found that pyrimidine pathway activity was elevated in the malignant epithelium of TNBC, within which we identified Epi4, a high-potency subpopulation coupling pyrimidine and folate metabolism and predicted to export folate. Furthermore, this folate was predicted to be taken up by FOLR2+ tumour-associated macrophages (TAMs) and was associated with S-adenosylmethionine(SAM)-dependent methylation signatures and MAFB activity. Spatially, Epi4 and FOLR2+ TAMs co-localised at the tumour\u2013stroma margin, a region of reduced T-cell density. DTYMK depletion reduced tumour fitness and attenuated folate-mediated macrophage reprogramming, which was largely restored by exogenous folate. Here, we therefore identify a DTYMK\u2013folate\u2013MAFB axis in which tumour metabolic rewiring is associated with epigenetic reprogramming of macrophages.<\/jats:p>","DOI":"10.3390\/ijms27198626","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:50:54Z","timestamp":1790614254000},"page":"8626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deoxythymidylate Kinase (DTYMK)-Driven Pyrimidine Hypermetabolism Is Associated with a Folate-Dependent Macrophage Programme in Triple-Negative Breast Cancer"],"prefix":"10.3390","volume":"27","author":[{"given":"Gaoge","family":"Peng","sequence":"first","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dequan","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-7032-1784","authenticated-orcid":false,"given":"Wucheng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Xin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifeng","family":"Hou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hefen","family":"Sun","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8456-3756","authenticated-orcid":false,"given":"Wei","family":"Jin","sequence":"additional","affiliation":[{"name":"Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai 200032, China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,26]]},"reference":[{"key":"ref_1","first-page":"7","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J. 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