Gu Min, Chen Weiwei, Ding Shizhen, Lin Zhijie, Qian Li, Xiao Weiming, Jia Xiaoqin, Lu Guotao, Gong Weijuan
Department of Basic Medicine, School of Medicine, Yangzhou University, Yangzhou, 225001, China.
Department of Gastroenterology, Affiliated Hospital, Yangzhou University, Yangzhou, 225001, China.
Cancer Immunol Immunother. 2025 Jul 25;74(9):277. doi: 10.1007/s00262-025-04104-1.
Gasdermin D (GSDMD), an effector molecule of cell pyroptosis, is known to be activated in various cells during inflammation. However, the patterns of GSDMD activation in immune regulatory cells such as myeloid-derived suppressor cells (MDSCs) remain unclear. In this study, we found that neutrophils in colorectal cancer (CRC) tissues exhibited reduced GSDMD transcription, as evidenced by a single-cell RNA sequencing result. Consistent with this, cleaved GSDMD expression is negatively correlated with S100A8 in CRC tissues. Additionally, CD15CD14LOX1 cells (G-MDSCs) from the peripheral blood of CRC patients exhibited a significant reduction in GSDMD activation. Mice with ubiquitous GSDMD deficiency bred in a clean environment exhibited a notable increase in G-MDSCs. These GSDMD MDSCs enhanced immunosuppressive activity by both inhibiting effector T-cell activity and promoting regulatory T-cell induction. This enhancement was also observed in GSDMD-S100A8 mice, in which GSDMD was specifically deleted in MDSCs. The tumor-promoting effects in the GSDMD and GSDMD-S100A8 mice were abrogated following MDSC depletion, as shown by the use of an anti-DR5 antibody. In the absence of GSDMD, G-MDSCs showed reduced inflammasome activation and decreased production of IL-1β and IL-18. Furthermore, a significant reduction in interferon-related factor 8/7 (IRF8/7) was observed in GSDMD G-MDSCs via bulk RNA sequencing analysis. After treatment with LPS/nigericin, these cells maintained mitochondrial integrity, thus impairing the mtDNA release and the downstream cGAS/STING/TBK1/IRF8/7 signaling axis activation. Reduced IRF8/7 levels were responsible for increased differentiation of GSDMD G-MDSCs. Finally, treatment with a GSDMD recombinant lentivirus injected into in situ tumors significantly inhibited tumor growth and reduced G-MDSC levels, suggesting that a GSDMD-based vaccine could simultaneously exert anti-carcinoma and anti-MDSC effects.
Gasdermin D（GSDMD）是细胞焦亡的效应分子，已知在炎症过程中可在多种细胞中被激活。然而，髓源性抑制细胞（MDSC）等免疫调节细胞中GSDMD的激活模式仍不清楚。在本研究中，我们发现结直肠癌（CRC）组织中的中性粒细胞表现出GSDMD转录减少，单细胞RNA测序结果证明了这一点。与此一致的是，CRC组织中裂解的GSDMD表达与S100A8呈负相关。此外，CRC患者外周血中的CD15⁺CD14⁻LOX1细胞（G-MDSC）表现出GSDMD激活显著降低。在清洁环境中培育的普遍存在GSDMD缺陷的小鼠表现出G-MDSC显著增加。这些GSDMD⁻ MDSC通过抑制效应T细胞活性和促进调节性T细胞诱导来增强免疫抑制活性。在GSDMD-S100A8小鼠中也观察到了这种增强，其中GSDMD在MDSC中被特异性缺失。如使用抗DR5抗体所示，在MDSC耗竭后，GSDMD和GSDMD-S100A8小鼠中的肿瘤促进作用被消除。在没有GSDMD的情况下，G-MDSC表现出炎性小体激活减少以及IL-1β和IL-18产生减少。此外，通过批量RNA测序分析在GSDMD⁻ G-MDSC中观察到干扰素相关因子8/7（IRF8/7）显著减少。用LPS/尼日利亚菌素处理后，这些细胞维持线粒体完整性，从而损害线粒体DNA释放和下游cGAS/STING/TBK1/IRF8/7信号轴激活。IRF8/7水平降低导致GSDMD⁻ G-MDSC分化增加。最后，向原位肿瘤注射GSDMD重组慢病毒进行治疗可显著抑制肿瘤生长并降低G-MDSC水平，这表明基于GSDMD的疫苗可同时发挥抗癌和抗MDSC作用。
