基于NLRP3炎症小体/IL-1β信号轴探讨铁死亡诱导剂Erastin抗癌新机制

IL-1β has been reported to promote tumor cell migration in non-small-cell lung cancer (NSCLC) via various mechanisms. Tumor-associated macrophages (TAMs) are important source of IL-1β in tumor immune microenvironment. TAMs are known to express and release IL-1β via NLRP3 inflammasome activation. In this study, we aimed to explore the possibility of inhibiting NSCLC metastasis by tightly regulating NLRP3 inflammasome/IL-1β axis in TAMs. Chemicals having both tumor cell cytotoxic effects and immunoregulatory effects deserve further investigation. Ferroptosis is a recently described form of programmed cell death. Erastin has been widely reported to induce ferroptosis in cancer cells with oncogenic Ras mutations. However, the effects of erastin on tumor immune microenvironment remain elusive. In this study, we found that erastin significantly downregulated IL-1β expression in TAMs isolated from Lewis lung cancer mice. Hence, we hypothesized that the ferroptosis inducer erastin would inhibit NSCLC metastasis via regulating NLRP3 inflammasome/IL-1β axis in TAMs. We would demonstrate the molecular mechanisms underlying the regulatory effects of erastin on NLRP3 inflammasome activation, and would explore the effects of erastin on NSCLC metastasis. And we'll have chance to provide a potential strategy for NSCLC treatment.

IL-1β可通过多种机制促进肿瘤细胞迁移。肿瘤相关巨噬细胞（TAM）可通过活化NLRP3炎症小体表达分泌IL-1β，是肿瘤免疫微环境IL-1β的重要来源。本课题旨在探索通过精密调控TAM NLRP3炎症小体/IL-1β轴抑制非小细胞肺癌转移的可能性。兼备肿瘤细胞杀伤作用与肿瘤免疫微环境调节作用的化合物值得深入研究。铁死亡是一种新近被报道的程序性细胞死亡方式。Erastin可诱导Ras突变的癌细胞发生铁死亡，但其对肿瘤免疫微环境的影响尚不明确。本课题前期结果表明，Erastin可显著下调小鼠Lewis肺癌TAM IL-1β的表达水平。因此，我们提出假说：铁死亡诱导剂Erastin可通过调控TAM NLRP3炎症小体/IL-1β轴抑制非小细胞肺癌转移。本课题将揭示Erastin调控NLRP3炎症小体活化的分子机制，及其对非小细胞肺癌转移的影响。本课题有可能为非小细胞肺癌的治疗提供潜在的新策略。

铁死亡诱导剂Erastin对肿瘤免疫微环境的影响及其机制尚不明确。本研究发现Erastin可通过影响肿瘤相关巨噬细胞（TAM）NLRP3炎症小体/IL-1β信号轴抑制肺癌转移。其中，经典凋亡蛋白FADD在下游IL-1β促肿瘤细胞迁移中发挥关键作用。Erastin对NLRP3炎症小体活化“信号1”和“信号2”均有抑制，且对“信号1”的抑制作用更强。转录组学分析表明，Erastin可通过多条通路影响TAM肿瘤免疫功能。细胞实验结果表明，Erastin可下调TAM表面转铁蛋白受体TfR1表达，促进TAM向具有抗肿瘤作用的M1型极化。体内研究表明，Erastin可安全有效地抑制小鼠Lewis肺癌生长，促进荷瘤小鼠脾脏结构及铁稳态正常化重塑。与之对应的是，Erastin可下调肿瘤组织NLRP3、IL1β及转铁蛋白受体TfR1和铁蛋白重链FtH表达水平。更为重要的是，Erastin可通过下调肺转移前微环境中M-MDSC和Ly6C(int) MHC II(-)单核细胞占比发挥抗肿瘤转移作用。TCGA泛癌分析结果表明，Erastin靶基因SLC7A11在多种癌症中高表达，以癌种特异性方式影响肿瘤免疫微环境并提示不良预后。此外，我们还发现，经典凋亡蛋白FADD参与调控髓系细胞铁死亡，具体机制值得后续深入研究。综上，本研究系统探索了铁死亡诱导剂Erastin对肿瘤免疫微环境的影响及分子机制，为铁死亡相关抗癌策略的临床应用提供了新的理论依据。