Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma

• Among patients relapsed or progressed after DP, CDP combination therapy is tolerable and highly effective.

• CDP therapy can relieve immunosuppression, increase immunogenicity, and enhance the killing of heterogenous HRS cell populations.

DNA methyltransferase inhibitor decitabine plus anti–programmed cell death 1 (DP) therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti–PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)–like cells. The classical CD30⁺ HRS-like cells interacted with abundant immunosuppressive IL21⁺CD4⁺ T helper cells, forming a positive feedback loop that supported their survival. While the CD30^– HRS-like cell population showed potential resistance to anti–PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8⁺ T cells and suppressed the proliferation of IL21⁺CD4⁺ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti–PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.