Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression PMID: 35794100

ADC Targets in Oncology

2026-04-10

Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression

Nat Commun. 2022 Jul 6;13(1):3882. doi: 10.1038/s41467-022-31417-x.

Xinyuan Lei ^# ¹ ² ³ , Hsinyu Lin ^# ¹ ³ , Jieqi Wang ^# ¹ ³ , Zhanpeng Ou ^# ¹ ³ , Yi Ruan ¹ ³ , Ananthan Sadagopan ⁴ ⁵ , Weixiong Chen ⁶ , Shule Xie ¹ ³ , Baisheng Chen ⁷ , Qunxing Li ¹ ³ , Jue Wang ⁸ , Huayue Lin ³ ⁹ , Xiaofeng Zhu ³ ⁹ , Xiaoqing Yuan ³ ⁹ , Tian Tian ¹⁰ , Xiaobin Lv ¹¹ ¹² , Sha Fu ⁸ , Xiaorui Zhu ¹³ , Jian Zhou ¹⁴ , Guokai Pan ¹ ³ , Xin Xia ¹ ³ , Bakhos A Tannous ¹⁵ , Soldano Ferrone ¹⁶ , Song Fan ¹⁷ ¹⁸ , Jinsong Li ¹⁹ ²⁰

Affiliations

1. Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China.
2. Molecular and Cellular Biology, State University of New York at Stony Brook, Stony Brook, NY, 11794, USA.
3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-Sen Memorial Hospital, Guangzhou, 510120, China.
4. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
5. Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
6. Department of Stomatology, Longgang District Central Hospital, Affiliated to Guangzhou University of Traditional Chinese Medicine, Shenzhen, 518116, China.
7. Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China.
8. Cellular Molecular Diagnostics Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China.
9. Breast Tumor Center, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China.
10. Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing, 211166, China.
11. Nanchang Key Laboratory of Cancer Pathogenesis and Translational Research, Center Laboratory, the Third Affiliated Hospital, Nanchang University, Nanchang, 330047, China.
12. Markey Cancer Center, the University of Kentucky, College of Medicine, Lexington, KY, 40506, USA.
13. Department of Chronic Diseases Epidemiology, Yale University of Public Health, New Haven, CT, 06520, USA.
14. Department of Medical Imaging, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
15. Experimental Therapeutics and Molecular Imaging Lab, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.
16. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. [email protected].
17. Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China. [email protected].
18. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-Sen Memorial Hospital, Guangzhou, 510120, China. [email protected].
19. Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, 510120, China. [email protected].
20. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation of Sun Yat-Sen Memorial Hospital, Guangzhou, 510120, China. [email protected].
# Contributed equally.

Abstract

Mitochondrial dynamics can regulate Major Histocompatibility Complex (MHC)-I antigen expression by Cancer cells and their immunogenicity in mice and in patients with malignancies. A crucial role in the mitochondrial fragmentation connection with immunogenicity is played by the IRE1α-XBP-1s axis. XBP-1s is a transcription factor for Aminopeptidase TPP2, which inhibits MHC-I complex cell surface expression likely by degrading tumor antigen peptides. Mitochondrial fission inhibition with Mdivi-1 upregulates MHC-I expression on Cancer cells and enhances the efficacy of adoptive T cell therapy in patient-derived tumor models. Therefore mitochondrial fission inhibition might provide an approach to enhance the efficacy of T cell-based immunotherapy.