Small-molecule MHC-II inducers promote immune detection and anti-cancer immunity via editing cancer metabolism

Ling Huang; Jun Zhang; Bo Wei; Shuangyang Chen; Sitong Zhu; Weiguan Qi; Xiaoying Pei; Lulu Li; Weiguang Liu; Yuzhi Wang; Xiaojun Xu; Lan-Gui Xie; Liming Chen

doi:10.1016/j.chembiol.2023.05.003

Small-molecule MHC-II inducers promote immune detection and anti-cancer immunity via editing cancer metabolism

Cell Chem Biol. 2023 Sep 21;30(9):1076-1089.e11. doi: 10.1016/j.chembiol.2023.05.003. Epub 2023 May 25.

Authors

Ling Huang¹, Jun Zhang¹, Bo Wei¹, Shuangyang Chen², Sitong Zhu³, Weiguan Qi², Xiaoying Pei¹, Lulu Li¹, Weiguang Liu¹, Yuzhi Wang⁴, Xiaojun Xu⁵, Lan-Gui Xie⁶, Liming Chen⁷

Affiliations

¹ Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China.
² Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210023, China.
⁴ Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
⁵ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210023, China. Electronic address: xiaojunxu@cpu.edu.cn.
⁶ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: xielg@njnu.edu.cn.
⁷ Department of Biochemistry, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China; Cancer Institute, School of Life Sciences, Nanjing Normal University, Nanjing 210023, China. Electronic address: chenliming1981@njnu.edu.cn.

PMID: 37236192
DOI: 10.1016/j.chembiol.2023.05.003

Abstract

Lack of MHC-II is emerging as a causal factor in cancer immune evasion, and the development of small-molecule MHC-II inducers is an unmet clinical need. Here, we identified three MHC-II inducers, including pristane and its two superior derivatives, that potently induce MHC-II expression in breast cancer cells and effectively inhibit the development of breast cancer. Our data suggest that MHC-II is central in promoting the immune detection of cancer to increase the tumor infiltration of T cells and enhance anti-cancer immunity. By discovering the malonyl/acetyltransferase (MAT) domain in fatty acid synthase (FASN) as the direct binding target of MHC-II inducers, we demonstrate that evasion of immune detection and cancer metabolic reprogramming are directly linked by fatty acid-mediated MHC-II silencing. Collectively, we identified three MHC-II inducers and illustrated that lack of MHC-II caused by hyper-activated fatty acid synthesis to limit immune detection is a potentially widespread mechanism underlying the development of cancer.

Keywords: MHC-II inducers; cancer immunity; cancer metabolism; immune detection; immunotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms*
Fatty Acids
Female
Histocompatibility Antigens Class II* / metabolism
Humans
T-Lymphocytes

Substances

Histocompatibility Antigens Class II
Fatty Acids