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In this study, we found that STAT1 enhanced the transcription of critical glycolytic enzymes, leading to an increase in lactate secretion from prostate cancer cells. Then, the lactate was transported to macrophages via the MCT1 transporter, activating the NF\u03baB1 pathway, which subsequently promoted macrophage polarization to the M2 phenotype and activated the transcription of MCP-1. MCP-1 was secreted from macrophages interacted with the CCR2 receptor on prostate cancer cells, thereby activating the JAK\/STAT1 pathway, ultimately contributing to the progression of prostate cancer and its resistance to radiotherapy. Taken together, our findings identified a STAT1\/lactate\/NF\u03baB1\/MCP-1 positive feedback mechanism as a driver of prostate cancer progression and resistance to radiotherapy that functioned by interaction to macrophages, which could be potential therapeutic targets for the advanced prostate cancer.<\/jats:p>","DOI":"10.1038\/s41419-026-08577-5","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T09:31:19Z","timestamp":1773912679000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A feedback mechanism from prostate cancer cells to macrophages, reinforced by STAT1, regulates tumor progression and resistance to radiotherapy"],"prefix":"10.1038","volume":"17","author":[{"given":"Jia-Yin","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Ting","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu-Yun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1571-6867","authenticated-orcid":false,"given":"Fei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ning","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wan-Jin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5324-3733","authenticated-orcid":false,"given":"Yong","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6461-7435","authenticated-orcid":false,"given":"Xue-Yi","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7426-6501","authenticated-orcid":false,"given":"Qing-Shui","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-7781","authenticated-orcid":false,"given":"Zhi-Bin","family":"Ke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-7025","authenticated-orcid":false,"given":"Ning","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,19]]},"reference":[{"key":"8577_CR1","first-page":"17","volume":"73","author":"RL Siegel","year":"2023","unstructured":"Siegel RL, Miller KD, Wagle NS, Jemal A. 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