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In this study, we used single-cell RNA sequencing to uncover substantial heterogeneity in the tumor microenvironments (TMEs) among patients received PD-1 inhibitor with partial response (PR), stable disease (SD), and that who underwent surgery without prior therapy. Notably, tumors classified as SD demonstrated an immunosuppressive environment, characterized by a higher prevalence of M2-like macrophages and lower frequencies of T and B cells, especially PD1<jats:sup>high<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells. These PD1<jats:sup>high<\/jats:sup>CD8<jats:sup>+<\/jats:sup> T cells were found to frequently engage with macrophages within the TMEs. Focusing on macrophages, we observed elevated expression of the Iron-Sulfur Cluster Assembly Enzyme (ISCU) in macrophages infiltrating SD tumors. ISCU was identified as a promoter of M2 macrophage polarization in a p53-dependent manner. Mechanistically, ISCU sequestrates p53 in the cytoplasm, reducing its nuclear location and relieving transcriptional repression of xCT and Arg1. Consequently, the increased expression of xCT and Arg1 modulates macrophage sensitivity to ferroptosis and the arginine metabolic pathway, thus affecting macrophage differentiation and inflammatory responses. Furthermore, inhibition of ISCU expression was found to repolarize macrophages, enhance CD8<jats:sup>+<\/jats:sup> T cell cytotoxicity, and boost the efficacy of anti-PD-1 antibody. Collectively, our findings highlight the complex interplay within ESCC TMEs and suggest that targeting ISCU might be a novel strategy to reprogram the immunosuppressive TME, potentially improving immunotherapy outcomes in ESCC patients.<\/jats:p>","DOI":"10.1038\/s41419-025-07787-7","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T12:15:57Z","timestamp":1750421757000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["ISCU-p53 axis orchestrates macrophage polarization to dictate immunotherapy response in esophageal squamous cell carcinoma"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0070-4131","authenticated-orcid":false,"given":"Jialiang","family":"Luo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"WeiTao","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxin","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujie","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9200-9317","authenticated-orcid":false,"given":"Guibin","family":"Qiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-8403","authenticated-orcid":false,"given":"Qingyun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"7787_CR1","doi-asserted-by":"publisher","first-page":"2074","DOI":"10.1056\/NEJMoa1112088","volume":"366","author":"P van Hagen","year":"2012","unstructured":"van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge, Henegouwen MI, et al. 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All authors have approved the manuscript and agree with its submission. We have no conflicts of interest to disclose.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"ESCC tumor samples in this study were approved by the Committees for the Ethical Review of Research Involving Human Subjects at the Guangdong Provincial People\u2019s Hospital. All animal experiments were approved by the Welfare and Ethical Committee for Experimental Animal Care of Southern Medical University. All methods were performed in accordance with the relevant guidelines and regulations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors reviewed the results and contributed to the final manuscript. All authors approved this manuscript for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}],"article-number":"462"}}