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In this study, we evaluate DNA methyltransferase (DNMT) inhibitors combined with anti\u2013PD-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\u2013PD-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\u2019 role in overcoming PD-1 resistance and support their combination with anti\u2013PD-1 as a promising strategy for R\/R NKTL.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Resistance to anti\u2013PD-1 immunotherapy remains a substantial challenge in R\/R NKTL. In this study, we reported that combining DNMT inhibitors with anti\u2013PD-1 mAb achieves a high complete response rate of 47.6% in immunotherapy-R\/R NKTL patients. Mechanistically, DNMT inhibitors potentiate anti\u2013PD-1 efficacy by triggering viral mimicry, remodeling the immune microenvironment and augmenting antitumor immunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-25-0587","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T04:02:51Z","timestamp":1760500971000},"page":"2450-2467","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed\/Refractory NK\/T-cell Lymphoma"],"prefix":"10.1158","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1358-6293","authenticated-orcid":false,"given":"Cheng","family":"Huang","sequence":"first","affiliation":[{"name":"1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, 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