尽管免疫检查点抑制剂（ICIs）彻底改变了癌症治疗的格局，但只有少数结直肠癌（CRC）患者对其有反应。通过增加主要组织相容性复合物 I (MHC-I) 表面表达来增强肿瘤免疫原性是增强 ICI 抗肿瘤功效的一种有前途的策略。进行双荧光素酶报告基因测定以寻找可以增加 MHC-I 表达的候选药物。通过双荧光素酶报告基因测定、qRT-PCR、流式细胞术和蛋白质印迹验证尼洛替尼对 MHC-I 表达的影响。通过一系列体外和体内实验评估了尼洛替尼的生物学功能。利用RNA-seq分析、免疫荧光分析、蛋白质印迹、流式细胞术、拯救实验和微阵列芯片分析，研究了潜在的分子机制。尼罗替尼诱导CRC细胞中MHC-I表达，增强CD8 T细胞的细胞毒性，从而增强抗肿瘤作用抗 PDL1 在微卫星不稳定性和微卫星稳定模型中的影响。从机制上讲，尼罗替尼通过 cGAS-STING-NF-κB 途径促进 MHC-I mRNA 表达，并通过抑制 CRC 细胞中 PCSK9 的表达来减少 MHC-I 降解。 PCSK9可能作为结直肠癌的潜在治疗靶点，尼罗替尼可能靶向PCSK9发挥抗结直肠癌作用。这项研究揭示了尼罗替尼通过诱导结直肠癌细胞中MHC-I表达而在抗肿瘤免疫中发挥以前未知的作用。我们的研究结果表明，尼洛替尼与抗 PDL1 疗法相结合可能是治疗 CRC 的有效策略。© 2024。作者。

Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs.Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated.Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects.This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.© 2024. The Author(s).