Li Leilei, Feng Qiang, Jiang Ya, Yang Lilin, Fang Hong, Xu Wenmang, Wang Yuanyuan, Pan Xinyan, Yang Julun
Graduate School, Kunming Medical University, Kunming, Yunnan, 650500, People's Republic of China.
Department of Pathology, 920 th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Rd, Kunming, Yunnan, 650032, People's Republic of China.
BMC Cancer. 2025 Sep 2;25(1):1417. doi: 10.1186/s12885-025-14336-0.
The imbalance of immune checkpoint molecules leads to immune escape of tumor cells. It has been established that KRAS mutation plays a key role in regulating PD-L1 expression of lung adenocarcinoma. However, the specific mechanism by which KRAS mutation regulates PD-L1 expression still needs further been clarified.
The relationship of KRAS mutation and ZNF24, SLC7A5 and PD-L1 expression in human lung adenocarcinoma tissues and cell lines were analyzed using relative assays. The effects of KRAS mutation on CD8 T cell-dependent anti-tumor immunity via the ZNF24/SLC7A5/PD-L1 axis were analyzed through in vitro and in vivo experiments. Additionally, we examined whether and how targeting ZNF24 inhibits KRAS mutation-induced PD-L1 expression and evaluated the effect of ZNF24 inhibition and PD-L1 blocking on CD8 T cell-dependent anti-tumor immunity.
Our results found that KRAS mutation increases the expression of PD-L1 through the ZNF24/SLC7A5 axis and simultaneously inhibits the activation of CD8 T cells in lung adenocarcinoma. Importantly, we discovered that Daptomycin (DAPT) binds to ZNF24 and inactivates it, representing the first reported inhibitor of ZNF24. DAPT combined with Anti PD-L1 monoclonal antibody may enhance CD8 T cell-dependent anti-tumor immunity in KRAS mutated lung adenocarcinoma.
Our study provides the first evidence that KRAS mutation promotes immune escape in lung adenocarcinoma through the ZNF24/SLC7A5/PD-L1 axis.
免疫检查点分子失衡导致肿瘤细胞免疫逃逸。已证实KRAS突变在调节肺腺癌PD-L1表达中起关键作用。然而，KRAS突变调节PD-L1表达的具体机制仍需进一步阐明。
采用相关检测方法分析人肺腺癌组织和细胞系中KRAS突变与ZNF24、SLC7A5及PD-L1表达的关系。通过体外和体内实验分析KRAS突变通过ZNF24/SLC7A5/PD-L1轴对CD8 T细胞依赖性抗肿瘤免疫的影响。此外，我们研究了靶向ZNF24是否以及如何抑制KRAS突变诱导的PD-L1表达，并评估了ZNF24抑制和PD-L1阻断对CD8 T细胞依赖性抗肿瘤免疫的作用。
我们的研究结果发现，KRAS突变通过ZNF24/SLC7A5轴增加PD-L1的表达，同时抑制肺腺癌中CD8 T细胞的激活。重要的是，我们发现达托霉素（DAPT）与ZNF24结合并使其失活，这是首次报道的ZNF24抑制剂。DAPT联合抗PD-L1单克隆抗体可能增强KRAS突变型肺腺癌中CD8 T细胞依赖性抗肿瘤免疫。
我们的研究首次提供证据表明，KRAS突变通过ZNF24/SLC7A5/PD-L1轴促进肺腺癌的免疫逃逸。
