Abstract A077: Estrogen-responsive fractions drive the immunosuppressive tumor microenvironment and immunotherapy resistance

Abstract Estrogen signaling plays a crucial role in cancer progression, yet its impact on the tumor microenvironment (TME) and immunotherapy outcomes remains poorly understood. This study investigated the influence of estrogen-responsive cell fractions on TME immunosuppression and immune checkpoint inhibitor (ICI) therapy resistance across diverse cancer types. Integrating growth factor-omics, single-cell RNA sequencing, and pan-cancer analysis, we identified two key estrogen-responsive malignant and cancer-associated fibroblast (CAF) cell fractions. These fractions consistently associated with immunosuppressive features across multiple cancer types, including reduced immune cell infiltration and increased regulatory T cell presence. Significantly, the estrogen-responsive CAF fraction strongly correlated with ICI therapy resistance in the majority of analyzed cohorts. These patients also exhibited the highest enrichment scores for immunosuppressive CAF markers, CAF.S1 and TGF-β CAF. Our findings reveal a common mechanism by which estrogen signaling influences tumor immunity and treatment outcomes across cancer types. The identification of FB.TNFSF10, an estrogen-responsive CAF fraction as a potential predictive biomarker for ICI resistance offers new opportunities for patient stratification and treatment optimization. This study provides a foundation for developing novel therapeutic strategies targeting estrogen-responsive cell fractions to enhance immunotherapy efficacy, potentially leading to more personalized and effective cancer treatments. Citation Format: Jin-Ke Lee, Kwanghwan Lee, Hyun Ju Kang. Estrogen-responsive fractions drive the immunosuppressive tumor microenvironment and immunotherapy resistance [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr A077.