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

  • Cell Chem Biol. 2023 May 22;S2451-9456(23)00126-5. doi: 10.1016/j.chembiol.2023.05.003.
Ling Huang  1 ,  Jun Zhang  1 ,  Bo Wei  1 ,  Shuangyang Chen  2 ,  Sitong Zhu  3 ,  Weiguan Qi  2 ,  Xiaoying Pei  1 ,  Lulu Li  1 ,  Weiguang Liu  1 ,  Yuzhi Wang  4 ,  Xiaojun Xu  5 ,  Lan-Gui Xie  6 ,  Liming Chen  7
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: [email protected].
  • 6. Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China. Electronic address: [email protected].
  • 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: [email protected].
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.
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13202
    T0070907
    99.98%, PPARγ Antagonist
    target: PPAR
    Research Areas: Cancer