PD-1/PD-L1靶向的免疫检查点阻断（ICB）治疗已经显示在肺癌中具有持久的临床效益。然而，许多患者对ICB治疗反应不佳，强调了我们对PD-L1调控和治疗抵抗的不完全理解。我们发现MTSS1在肺腺癌中下调，导致PD-L1上调、CD8+淋巴细胞功能受损和增强肿瘤进展。MTSS1下调与患者ICB疗效改善相关。机械上，MTSS1与E3连接酶AIP4相互作用，对PD-L1在赖氨酸263位单泛素化，导致PD-L1内吞信号传导及溶酶体降解。此外，EGFR-KRAS信号在肺腺癌中抑制MTSS1且上调PD-L1。更重要的是，通过临床抗抑郁药物克劳米普拉明靶向AIP4和ICB治疗的结合可以改善治疗反应并有效抑制免疫竞争力小鼠和人源化小鼠中ICB抗性肿瘤的生长。总的来说，我们的研究发现了MTSS1-AIP4轴用于PD-L1的单泛素化，并揭示了潜在的抗抑郁药物和ICB联合治疗。 ©2023作者。

Immune checkpoint blockade (ICB) therapy targeting PD-1/PD-L1 has shown durable clinical benefits in lung cancer. However, many patients respond poorly to ICB treatment, underscoring an incomplete understanding of PD-L1 regulation and therapy resistance. Here, we find that MTSS1 is downregulated in lung adenocarcinoma, leading to PD-L1 upregulation, impairment of CD8+ lymphocyte function, and enhanced tumor progression. MTSS1 downregulation correlates with improved ICB efficacy in patients. Mechanistically, MTSS1 interacts with the E3 ligase AIP4 for PD-L1 monoubiquitination at Lysine 263, leading to PD-L1 endocytic sorting and lysosomal degradation. In addition, EGFR-KRAS signaling in lung adenocarcinoma suppresses MTSS1 and upregulates PD-L1. More importantly, combining AIP4-targeting via the clinical antidepressant drug clomipramine and ICB treatment improves therapy response and effectively suppresses the growth of ICB-resistant tumors in immunocompetent mice and humanized mice. Overall, our study discovers an MTSS1-AIP4 axis for PD-L1 monoubiquitination and reveals a potential combinatory therapy with antidepressants and ICB.© 2023. The Author(s).