NAT10 promotes radiotherapy resistance in non-small cell lung cancer by regulating KPNB1-mediated PD-L1 nuclear translocation.

Abstract

Radiotherapy (RT) resistance in non-small cell lung cancer (NSCLC) is a significant contributor to tumor recurrence. NAT10, an enzyme that catalyzes ac4C RNA modification, has an unclear role in RT resistance. This study aimed to explore the function of NAT10 in RT resistance in NSCLC. RT-resistant NSCLC cell lines (PC9R and A549R) were established through repeated irradiation. The impact of NAT10 on cellular immunity was evaluated by measuring immune cell populations, cytotoxicity levels, and markers of cell dysfunction. Results demonstrated elevated levels of ac4C and NAT10 in RT-resistant cells. Knockdown of NAT10 suppressed cell proliferation and enhanced immune function in PC9R and A549R cells by upregulating TNF-α and IFN-γ while downregulating PD-1 and TIM-3. Mechanistically, RT resistance in NSCLC was mediated by NAT10-dependent ac4C modification of KPNB1. Furthermore, KPNB1 facilitated PD-L1 nuclear translocation, promoting immune escape in RT-resistant NSCLC cells. Overexpression of KPNB1 enhanced cell proliferation but impaired immune function in RT-resistant NSCLC cells. In conclusion, this study demonstrates that NAT10 upregulates KPNB1 expression through ac4C modification, thereby promoting RT resistance in NSCLC via PD-L1 nuclear translocation. These findings reveal a novel mechanism underlying RT resistance in NSCLC.