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In melanoma, vitiligo\u2010like depigmentation is a frequent and generally mild immune\u2010related adverse event, whose presence correlates positively with enhanced antitumor immune responses and prolonged patient survival. By performing comparative analyses between vitiligo and melanoma, we established a biomarker panel\u2014designated the vitiligo signature (VGS)\u2014that differentiates \u201ccold\u201d from \u201chot\u201d tumors with high accuracy. Leveraging a deep learning\u2013based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti\u2013programmed cell death ligand 1 (PD L1) therapy in preclinical models. Single cell RNA sequencing revealed that Fulvestrant expanded cytotoxic T cell populations, while immunofluorescence and flow cytometry confirmed markedly increased CD8\u207a T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C\u2500C motif chemokine 5 (CCL5), major histocompatibility complex class I (MHC I), and type II interferon (IFN II) signaling pathways, thereby potentiating antitumor immunity. Collectively, our study introduces a precision approach for patient stratification in immunotherapy and highlights Fulvestrant as a promising component of immunotherapy based combination strategies warranting clinical evaluation.<\/jats:p>","DOI":"10.1002\/advs.202503979","type":"journal-article","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T14:50:21Z","timestamp":1758379821000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Vitiligo Signature\u2010Based Drug Screening Identifies Fulvestrant as a Novel Immunotherapy Combination Strategy"],"prefix":"10.1002","volume":"12","author":[{"given":"Jie","family":"Zhu","sequence":"first","affiliation":[{"name":"Institute of Translational Medicine The Affiliated Hospital of Qingdao University College of Medicine Qingdao University Qingdao 266071 P. R. 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