Aging increases ovarian cancer growth, metastasis and immunosuppression that can be alleviated by inhibiting hedgehog signaling

Ovarian cancer incidence and mortality increase with age, yet the impact of physiological aging on tumor progression and the tumor immune microenvironment remains poorly defined. Here we show using orthotopic implantation of two syngeneic models representing distinct cellular origins (ovarian surface epithelial and fallopian tube-derived) in young versus aged mice, that aged hosts exhibit markedly higher tumor burden, ascites accumulation, and proliferation. Selective follicle depletion in young mice using VCD did not recapitulate these effects, indicating that age-associated microenvironmental changes beyond hormonal decline drive tumor growth. Spatial transcriptomics revealed distinct intratumoral heterogeneity in both age groups. Comparison of CD45+ cells between aged and young tumors showed Hedgehog signaling enrichment and immunosuppressive signatures in aged hosts, with elevated M2 macrophages and Foxp3+ regulatory T cells. Notably, pharmacologic inhibition of Hedgehog signaling with vismodegib in aged mice suppressed tumor growth, reduced metastatic spread, and decreased infiltration of CD206+ macrophages and Foxp3+ T cells while sparing CD8+ T cells. Our findings provide proof-of-concept that vismodegib can reduce tumor growth and specific immunosuppressive populations in aged hosts, suggesting Hedgehog inhibition as a potential immunomodulatory strategy for older ovarian cancer patients or those tumors that exhibit Hedgehog pathway activation.