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  3. Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFN-γ-ΙRF1-SREBF2 Axis

Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFN-γ-ΙRF1-SREBF2 Axis

  • Cancer Immunol Res. 2025 Dec 9. doi: 10.1158/2326-6066.CIR-25-0242.
Liping Xu 1,  Xiaomin Zhang 1,  Xiaowei Lai 2,  Hongyuan Chen 3,  Shuangye Liao 1,  Mingzeng Chang 1,  Xiaoqing Wu 3,  Wen Rui 3,  Juan Yang 4,  Danyang Wang 2,  Chengqi Gao 5,  Ziqian Fang 6,  Jianeng Zhang 6,  Wende Li 7,  Bo Li 8,  Xiaojun Xia 1,  Penghui Zhou 1
Affiliations

Affiliations

  • 1 Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 2 Sun Yat-sen University Cancer Center, China.
  • 3 Guangdong Pharmaceutical University, Guangzhou, China.
  • 4 Hunan University of Medicine, Hunan, China.
  • 5 Nanchang University, Nanchang, Jiangxi, China.
  • 6 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, China.
  • 7 Guangdong Laboratory Animals Monitoring Institute, China.
  • 8 Southern Medical University, Guangzhou, China.
PMID: 41364085 DOI: 10.1158/2326-6066.CIR-25-0242
Abstract

Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. Here, we demonstrated that anti-PD-1 treatment regulated Cholesterol biosynthesis in Cancer cells through the effector cytokine interferon IFN-γ. Mechanistically, IFN-γ-induced IRF1 transcriptionally suppresses the expression of SREBF2, a master regulator of Cholesterol synthesis. Reduced Cholesterol content inhibited tumor growth and sensitized tumor cells to statins, drugs lowering Cholesterol. Overall, our study reveals that IFN-γ-mediated inhibition of Cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.

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