Priming with DNMT inhibitors potentiates PD-1 immunotherapy by triggering viral mimicry in relapsed/refractory NK/T-cell lymphoma

Anti-PD-1 immunotherapy has demonstrated significant anti-tumor efficacy in treating relapsed or refractory natural killer/T cell lymphoma (R/R NKTL). However, both intrinsic and acquired resistance remain a substantial challenge. DNA hypermethylation serves as a critical epigenetic modifier influencing anti-tumor immunity in NKTL. Here, we evaluate the efficacy and safety of combining DNA methyltransferase (DNMT) inhibitors with anti-PD-1 monoclonal antibody (mAb) as salvage therapy in 21 patients with R/R NKTL who had previously failed frontline immunotherapy. This combination therapy achieved an objective response rate (ORR) of 66.7% (14/21), with a complete response (CR) rate of 47.6% (10/21), and a 2-year overall survival (OS) rate of 50.2%. To investigate the mechanisms underlying the therapeutic efficacy of this combination, we established a preclinical xenograft model of acquired resistance to anti-PD-1 therapy. Our findings revealed that resistance to anti-PD-1 treatment was characterized by the absence of CD8+ T-cell infiltration and the inactivation of interferon pathways. In contrast, DNMT inhibitors restored CD8+ T-cell infiltration, and sensitized tumors to anti-PD-1 therapy. Mechanistically, DNMT inhibitors induced DNA demethylation of endogenous retroviral elements (ERVs), leading to the upregulation of endogenous nucleic acid expression and the activation of a viral mimicry response. This response subsequently triggered the type I interferon pathway, thereby enhancing anti-tumor immunity in both murine and human T-cell lymphoma models. Collectively, our study highlights the potential of DNMT inhibitors in restoring tumor sensitivity to anti-PD-1 therapy and provides compelling evidence for combining DNMT inhibitors with anti-PD-1 mAb as a promising therapeutic strategy for R/R NKTL.