Spatial multi-omics reveal spatially coordinated cholesterol metabolic programs in castration-resistant prostate cancer

Progression to castration-resistant prostate cancer (CRPC) involves critical biological changes that drive therapeutic resistance. Although systemic cholesterol metabolism has been implicated in prostate cancer progression, how cholesterol metabolic programs are spatially organized within the tumor microenvironment during CRPC evolution remains poorly understood. We analyzed longitudinal clinical data from a prospective cohort of 199 patients with advanced prostate cancer to examine systemic cholesterol dynamics during progression to CRPC. To investigate tissue-level mechanisms, we performed paired single-cell-resolution spatial multi-omics analyses of hormone-sensitive prostate cancer (HSPC) and matched CRPC specimens from the same patients, enabling cell-type–resolved analysis of cholesterol metabolic programs across tumor and stromal components. Longitudinal clinical analysis showed that greater increases in serum total cholesterol over time, rather than baseline levels, were significantly associated with a higher risk of progression to CRPC. Spatial multi-omics profiling revealed heterogeneous tumor cholesterol acquisition strategies, including increased expression of SCARB1 , alongside expansion of stromal populations with cholesterol efflux–associated transcriptional programs. Notably, spatial analyses demonstrated preferential localization of cholesterol import-dominant tumor cells in proximity to efflux-active macrophages and fibroblasts, consistent with supporting spatial associations between tumor metabolic states and cholesterol efflux-related stromal programs. These findings support a model of a spatially organized cholesterol metabolic landscape in CRPC and identify coordinated associations between tumor metabolic states and stromal cholesterol-efflux programs during disease progression. This framework provides insight into metabolic adaptation in advanced prostate cancer and suggests potential therapeutic opportunities for future investigation.