Fan Fanfan, Wang Jun, Liu Kun, Zhang Shiyue, Gao Jian, Li Xiongfei, Ma Jiaqiang, Zhao Yue, Li Teng, Su Han, Yang Xinfeng, Han Han, Huang Qingyuan, Zhang Yiliang, Pan Yunjian, Ye Ting, Hu Hong, Sun Yihua, Li Fei, Cao Zhiwei, Zhang Yang, Zhang Xiaoming, Chen Haiquan
Department of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Shanghai, China.
Institute of Thoracic Oncology, Fudan University, Shanghai, China.
Nat Commun. 2025 Jul 2;16(1):6074. doi: 10.1038/s41467-025-61324-w.
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.
肥大细胞（MC）在免疫反应和炎症调节中起着关键的哨兵作用，但其在肺腺癌（LUAD）中的功能在很大程度上仍被忽视。为了解码其异质性，我们对LUAD浸润的MC进行了单细胞转录组分析。我们的研究揭示了MC组成的复杂性，并确定了9种不同状态，包括促炎、趋化和抗原呈递。以高IL-18表达为特征的促炎MC亚群与LUAD患者的较好预后相关。这种促炎特性由MC内NLRP3炎性小体的激活调节，导致GSDMD孔的形成和连续的焦亡。此外，这些MC通过细胞因子激活机制上调NKG2D和IFN-γ，增强MAIT细胞的固有样抗肿瘤活性。我们的结果揭示了MC的一种未被认识的状态，并描述了LUAD中炎性小体依赖性、MC介导的MAIT细胞调节。这些发现使我们对MC和MAIT细胞的功能库和机制有了更丰富的理解，并为癌症治疗提出了一个潜在的治疗靶点。
