Abstract

Cholesterol metabolism influences prostate cancer (PCa) progression, especially by affecting the tumor microenvironment. The present study demonstrated that cancer cell-intrinsic cholesterol promoted the S-palmitoylation of specificity protein 1 (SP1), enhancing SP1 nuclear translocation and driving the transcription and secretion of midkine (MDK), which in turn facilitated the differentiation of macrophages into a lipid-associated phenotype. Furthermore, targeting cholesterol metabolism with simvastatin significantly reduced MDK levels, inhibited immunosuppressive macrophage polarization, and enhanced the efficacy of enzalutamide in vivo. These findings suggested that targeting the cancer cell-intrinsic cholesterol-induced immunosuppressive tumor microenvironment could be an effective strategy to improve therapeutic outcomes in prostate cancer patients.