Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory NK/T-cell Lymphoma

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.