The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. This study in orthotopic GBM models in male mice identifies that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1) restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. An ApoA1-armed oncolytic adenovirus restores antitumor immunity and elicits long-term tumor-specific immune surveillance. The findings provide insight into how cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances.
