Mast cells boost anti-tumor potency of MAIT cells via inflammasome-dependent secretion of IL-18

  • Nat Commun. 2025 Jul 2;16(1):6074. doi: 10.1038/s41467-025-61324-w.
Fanfan Fan  #  1  2  3  4 ,  Jun Wang  #  5 ,  Kun Liu  #  6 ,  Shiyue Zhang  #  5 ,  Jian Gao  #  1  2  3  5 ,  Xiongfei Li  1  2  3  4 ,  Jiaqiang Ma  7 ,  Yue Zhao  1  2  3 ,  Teng Li  4 ,  Han Su  4 ,  Xinfeng Yang  4 ,  Han Han  1  2  3 ,  Qingyuan Huang  1  2  3 ,  Yiliang Zhang  1  2  3 ,  Yunjian Pan  1  2  3 ,  Ting Ye  1  2  3 ,  Hong Hu  1  2  3 ,  Yihua Sun  1  2  3 ,  Fei Li  6 ,  Zhiwei Cao  8 ,  Yang Zhang  9  10  11 ,  Xiaoming Zhang  12 ,  Haiquan Chen  13  14  15
Affiliations
  • 1. Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.
  • 2. Institute of Thoracic Oncology, Fudan University, Shanghai, China.
  • 3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
  • 4. The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China.
  • 5. School of Life Sciences, Fudan University, Shanghai, China.
  • 6. Department of Pathology and Frontier Innovation Center, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 7. Department of Liver Surgery and Transplantation, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 8. School of Life Sciences, Fudan University, Shanghai, China. [email protected].
  • 9. Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 10. Institute of Thoracic Oncology, Fudan University, Shanghai, China. [email protected].
  • 11. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • 12. The Center for Microbes, Development and Health, Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 13. Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China. [email protected].
  • 14. Institute of Thoracic Oncology, Fudan University, Shanghai, China. [email protected].
  • 15. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 40603850 DOI: 10.1038/s41467-025-61324-w
Abstract

Mast cells (MC) serve as pivotal sentinels in the regulation of immune responses and inflammation, yet their function in lung adenocarcinoma (LUAD) remains largely neglected. To decode their heterogeneity, we perform single-cell transcriptomic analysis of LUAD-infiltrating MCs. Our study uncovers the complexity in MC composition and identifies 9 distinct states, including proinflammation, chemotaxis, and antigen presentation. The proinflammatory MC subset, characterized by high IL-18 expression, is associated with improved outcomes for LUAD patients. This pro-inflammatory property is regulated by the activation of NLRP3 inflammasome within MCs, resulting in the formation of GSDMD pores and successive Pyroptosis. Moreover, these MCs enhance the innate-like anti-tumor activity of MAIT cells by upregulating NKG2D and IFN-γ through the cytokine-activation mechanism. Our results uncover an unappreciated state of MCs and describe an inflammasome-dependent, MC-mediated regulation of MAIT cells in LUAD. These findings diversify our understanding of the functional repertoire and mechanistic equipment of MCs and MAIT cells, and suggest a potential therapeutic target for Cancer treatment.

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