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Priming with DNMT Inhibitors Potentiates PD-1 Immunotherapy by Triggering Viral Mimicry in Relapsed/Refractory
Cheng Huang1,2, Yan Gao1, Jianfeng Chen1
1State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
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.
Insights
Combining DNA methyltransferase inhibitors with anti-PD-1 therapy shows promise for relapsed or refractory NK/T-cell lymphoma patients resistant to immunotherapy. This approach restores immune response and improves survival rates.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Anti-PD-1 immunotherapy offers significant antitumor effects in relapsed or refractory NK/T-cell lymphoma (R/R NKTL).
- Resistance to anti-PD-1 therapy is a major obstacle in R/R NKTL treatment.
- Understanding mechanisms of resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To evaluate the efficacy of combining DNA methyltransferase (DNMT) inhibitors with anti-PD-1 monoclonal antibody (mAb) in R/R NKTL patients who failed prior immunotherapy.
- To elucidate the underlying mechanisms by which DNMT inhibitors overcome anti-PD-1 resistance.
Main Methods:
- A clinical study involving 21 R/R NKTL patients treated with DNMT inhibitors plus anti-PD-1 mAb.
- Preclinical models were used to investigate the molecular mechanisms of resistance and the effects of DNMT inhibitors.
- Analysis of immune cell infiltration (CD8+ T-cells), IFN pathways, DNA demethylation, and endogenous nucleic acid expression.
Main Results:
- The combination therapy achieved an objective response rate of 66.7% and a complete response rate of 47.6%.
- Two-year overall survival rate was 50.2% in the treated patient cohort.
- DNMT inhibitors reversed anti-PD-1 resistance by restoring CD8+ T-cell infiltration and IFN pathway activity, potentially through viral mimicry.
Conclusions:
- Combination of DNMT inhibitors with anti-PD-1 mAb is a promising strategy for R/R NKTL patients with prior immunotherapy failure.
- DNMT inhibitors enhance anti-PD-1 efficacy by promoting immune microenvironment remodeling and augmenting antitumor immunity via viral mimicry.
- This combination approach offers a potential breakthrough for overcoming immunotherapy resistance in R/R NKTL.
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