Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma
Cheng Huang, Yan Gao, Jianfeng Chen, Jing Han Hong, Yue Jiang, Kelila Xin Ye Chai, Yingxi Li, Peili Wang, Yali Wang, Jiuping Gao, Xian Zeng, R. Xiao, Haixia He, Peiyong Guan, Jason Yongsheng Chan, Jing Quan Lim, Anand D. Jeyasekharan, Dachuan Huang, Jin‐Xin Bei, Bin Tean Teh, Soon Thye Lim, Qiang Yu, Choon Kiat Ong, Huiqiang Huang, Jing Tan
Abstract
Anti-PD-1 immunotherapy has demonstrated significant antitumor efficacy in relapsed or refractory NK/T-cell lymphoma (R/R NKTL), but resistance remains a substantial challenge. In this study, we evaluate DNA methyltransferase (DNMT) inhibitors combined with anti-PD-1 mAb in 21 patients with R/R NKTL for whom prior immunotherapy failed. This combination therapy achieved an objective response rate of 66.7% (14/21), with a complete response rate of 47.6% (10/21) and a 2-year overall survival rate of 50.2%. Preclinical models revealed that anti-PD-1 resistance was linked to the absence of CD8+ T-cell infiltration and suppressed IFN pathways. DNMT inhibitors reversed these effects, restoring CD8+ T-cell activities and tumor sensitivity to PD-1 blockade. Mechanistically, DNMT inhibitors triggered DNA demethylation of endogenous retroviral elements, activating viral mimicry via upregulated endogenous nucleic acids and type I IFN signaling. These findings underscore DNMT inhibitors' role in overcoming PD-1 resistance and support their combination with anti-PD-1 as a promising strategy for R/R NKTL. SIGNIFICANCE: Resistance to anti-PD-1 immunotherapy remains a substantial challenge in R/R NKTL. In this study, we reported that combining DNMT inhibitors with anti-PD-1 mAb achieves a high complete response rate of 47.6% in immunotherapy-R/R NKTL patients. Mechanistically, DNMT inhibitors potentiate anti-PD-1 efficacy by triggering viral mimicry, remodeling the immune microenvironment and augmenting antitumor immunity.