Targeting Tumor Immunity: Statins as a Repurposed Strategy for Preventing Ovarian Cancer Advancement

Abstract

High-grade serous ovarian carcinoma (HGSOC) remains the most lethal gynecologic malignancy, characterized by a high recurrence rate and poor long-term survival. Although daily statin use is associated with improved survival in ovarian cancer patients, the underlying mechanism of this benefit remains unclear, in part due to the use of non-clinical high doses and reliance on immunodeficient murine models in preclinical studies. Here, we analyzed data from the TriNetX US Collaborative Network to evaluate the association between statin use and survival in ovarian cancer patients, confirming a survival benefit in a large U.S. cohort. We next investigated the protective effects in a syngeneic ascites tumor model of ovarian cancer. Mice treated with clinically relevant doses of lipophilic atorvastatin (ATO) exhibited prolonged survival. Single-cell transcriptomic analyses further revealed enhanced CD8+ T-cell activation programs and pro-inflammatory macrophage remodeling. Flow cytometry identified increased M1-like macrophages and activated CD8+ T-cell populations. Cytokine profiling and transcriptomic analyses indicated that IL-15 signaling was significantly elevated following ATO treatment. Multiplex immunofluorescence analyses demonstrated enhanced tertiary lymphoid structure (TLS)-associated immune organization in metastatic tumor tissues after ATO treatment, with increased T- and B-cell markers. Ex vivo culture of primary T cells with ascites supernatant from ATO-treated mice resulted in enhanced T-cell activation and migratory capacity compared with supernatant from DMSO-treated mice. Collectively, our results suggest that daily statin use may remodel the body environment into a more immune-activated state, leading to a long-term beneficial effect on survival in cancer patients, as observed in large epidemiological studies.