通过稳定p53蛋白水平诱导携带STK11突变非小细胞肺癌多重程序性死亡机制探索相关研究

在免疫治疗彻底改变非小细胞肺癌治疗格局的同时，仍有大量患者无法获得理想的治疗效果，其中，多项研究表明STK11突变与非小细胞肺癌免疫治疗耐药相关。本项目研究证实，携带STK11突变的细胞株对多种MDM2抑制剂敏感，其可以通过稳定细胞内p53蛋白浓度，诱导肿瘤细胞发生凋亡及铁死亡双重程序性死亡事件，经由MDM2-P53中枢分别从HIF1-mTOR及pSTAT3-SLC7A11相关信号通路，逆转STK11突变导致的凋亡抵抗及肿瘤细胞对还原态底物的依赖。此外，在免疫浸润微环境方面，P53可以通过抑制pSTAT-IL6途径改善STK11突变导致的肿瘤相关中性粒细胞浸润水平，逆转其对免疫治疗的耐药抵抗。本研究围绕STK11耐药抵抗相关机制及探讨潜在治疗方案为相关患者提供针对性治疗方案。

While immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer, there are still a large number of patients who are unable to achieve the desired therapeutic outcome. Among them, several studies have shown that STK11 mutations are associated with immunotherapy resistance in non-small cell lung cancer. In this project, we demonstrated that cell lines carrying STK11 mutations are sensitive to various MDM2 inhibitors, which can induce dual programmed death events of apoptosis and iron death in tumor cells by stabilizing intracellular p53 protein concentrations, and reversing STK11 resistance and iron death through the HIF1-mTOR and pSTAT3-SLC7A11-related signaling pathways via the MDM2-P53 hub, respectively. mutations resulted in apoptosis resistance and tumor cell dependence on reduced state substrates. In addition, in the immune infiltration microenvironment, P53 could improve the level of tumor-associated neutrophil infiltration caused by STK11 mutations and reverse their resistance to immunotherapy by inhibiting the pSTAT-IL6 pathway. This study focuses on the mechanisms related to STK11 drug resistance and explores potential therapeutic options to provide targeted treatment options for the patients concerned.