2. Academic Validation
  3. Cancer Cell-Intrinsic Cholesterol Induces Lipid-Associated Macrophage Differentiation via SP1 Palmitoylation to Promote Prostate Cancer Progression

Cancer Cell-Intrinsic Cholesterol Induces Lipid-Associated Macrophage Differentiation via SP1 Palmitoylation to Promote Prostate Cancer Progression

  • Adv Sci (Weinh). 2026 Apr;13(19):e08588. doi: 10.1002/advs.202508588.
Shirong Peng 1 2,  Weilong Lin 1 2,  Zean Li 1 2,  Ruilin Zhuang 1 2,  Shengmeng Peng 1 2,  Bingheng Li 1 2,  Bingliang Chen 1 2,  Yong Luo 1 2,  Yuan Ou 1 2,  Wei Zhuang 3,  Tao Du 4,  Kaiwen Li 1 2,  Hai Huang 1 2 5 6
Affiliations

Affiliations

  • 1 Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
  • 2 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Urology Department, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 3 Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
  • 4 Department of Obstetrics and Gynecology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
  • 5 Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
  • 6 Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China.
PMID: 41603134 DOI: 10.1002/advs.202508588
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.

Keywords

Lipid‐associated macrophages; Specificity protein 1; S‐palmitoylation; cholesterol; midkine.

Figures
Products