Immunotherapy Inhibits Tumor Cholesterol Synthesis via the IFNγ–IRF1–SREBF2 Axis
Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. In this study, we demonstrated that anti-PD-1 treatment regulated cholesterol biosynthesis in cancer cells through the effector cytokine IFNγ. Mechanistically, IFNγ-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 that can lower cholesterol. Overall, our study reveals that IFNγ-mediated inhibition of cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.
Authors
- Wen Rui (ORCID: https://orcid.org/0000-0002-1616-0469)
- Danyang Wang (ORCID: https://orcid.org/0000-0003-4540-6656)
- Xiaojun Xia (ORCID: https://orcid.org/0000-0003-4444-7472)
- Xiaomin Zhang (ORCID: https://orcid.org/0000-0003-4368-8629)
- Wende Li (ORCID: https://orcid.org/0000-0003-0097-7308)
- Penghui Zhou (ORCID: https://orcid.org/0000-0003-3000-3133)
- Changjun Gao (ORCID: https://orcid.org/0009-0003-3708-7306)
- Shuangye Liao (ORCID: https://orcid.org/0000-0001-9509-7025)
- Liping Xu (ORCID: https://orcid.org/0000-0003-3370-2386)
- Jianeng Zhang (ORCID: https://orcid.org/0000-0001-8225-6031)
- Ziqian Fang (ORCID: https://orcid.org/0000-0002-1897-540X)
- Hongyuan Chen (ORCID: https://orcid.org/0000-0002-6817-9073)
- Bo Li (ORCID: https://orcid.org/0000-0002-7979-8339)
- Xiaoqing Wu (ORCID: https://orcid.org/0009-0009-1620-3885)
- Juan Yang
- Xiaowei Lai (ORCID: https://orcid.org/0009-0007-0672-1326)
- M L Chang (ORCID: https://orcid.org/0009-0006-5616-5551)
Institutions
- Nanchang University (CN)
- Hunan University of Traditional Chinese Medicine (CN)
- Sun Yat-sen University (CN)
- Hunan University (CN)
- Guangdong Pharmaceutical University (CN)
- Hunan University of Science and Engineering (CN)
- Guangdong Laboratory Animals Monitoring Institute (CN)
- Sun Yat-sen University Cancer Center (CN)
- State Key Laboratory of Oncology in South China
- Southern Medical University (CN)
Publication Details
- Journal
- Cancer Immunology Research
- Published
- 2025-12-09
- DOI
- https://doi.org/10.1158/2326-6066.cir-25-0242
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00