Vitiligo Signature‐Based Drug Screening Identifies Fulvestrant as a Novel Immunotherapy Combination Strategy

A vitiligo‐derived gene signature predicts response to immune checkpoint blockade across multiple cancer cohorts, providing a framework for patient stratification. Building on this, Fulvestrant—a clinically approved estrogen receptor degrader—further enhances antitumor immunity by reprogramming tumor‐associated macrophages and promoting CD8⁺ T cell infiltration, suggesting a potential combination strategy to improve immunotherapy efficacy. Abstract Immunotherapy has revolutionized cancer treatment; however, only 10–30% of patients experience durable survival benefits, while most malignancies remain resistant. In melanoma, vitiligo‐like depigmentation is a frequent and generally mild immune‐related 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—designated the vitiligo signature (VGS)—that differentiates “cold” from “hot” tumors with high accuracy. Leveraging a deep learning–based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti–programmed 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⁺ T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C─C 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. A vitiligo-derived gene signature predicts response to immune checkpoint blockade across multiple cancer cohorts, providing a framework for patient stratification. Building on this, Fulvestrant—a clinically approved estrogen receptor degrader—further enhances antitumor immunity by reprogramming tumor-associated macrophages and promoting CD8⁺ T cell infiltration, suggesting a potential combination strategy to improve immunotherapy efficacy. Abstract Immunotherapy has revolutionized cancer treatment; however, only 10–30% of patients experience durable survival benefits, while most malignancies remain resistant. In melanoma, vitiligo-like depigmentation is a frequent and generally mild immune-related 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—designated the vitiligo signature (VGS)—that differentiates “cold” from “hot” tumors with high accuracy. Leveraging a deep learning–based efficacy prediction system (DLEPS), we identified and validated Fulvestrant as a candidate capable of enhancing anti–programmed 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⁺ T cell infiltration into tumor tissue. Mechanistic investigations demonstrated that Fulvestrant activates the C─C 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. Advanced Science, Volume 12, Issue 44, November 27, 2025.