Chidamide synergizes with cisplatin-etoposide to trigger pyroptosis and anti-tumor immunity in diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy where many patients relapse after standard therapy, necessitating novel approaches. Pyroptosis is an inflammatory cell death that can stimulate antitumor immunity. Histone deacetylases are frequently overexpressed in DLBCL and contribute to immune evasion. This study investigates whether combining the HDAC inhibitor chidamide with cisplatin and etoposide induces pyroptosis and enhances antitumor immune responses. We evaluated chidamide combined with cisplatin and etoposide in diffuse large B-cell lymphoma cell lines and syngeneic mouse models. Cell death mechanisms were analyzed using immunoblotting and imaging. Tumor growth and immune cell infiltration were assessed in immunocompetent mice, with the role of adaptive immunity evaluated through CD8-positive T cell depletion. Statistical analyses included analysis of variance where appropriate. Here we show that chidamide synergistically potentiates cisplatin and etoposide efficacy by upregulating gasdermin E expression and promoting its caspase-3-dependent cleavage, thereby triggering pyroptosis. This combination remodels the tumor microenvironment, increasing infiltration of dendritic cells, natural killer cells, and CD8-positive T cells while reducing immunosuppressive macrophages. Depletion of CD8-positive T cells abolishes the therapeutic benefit, demonstrating their essential role. The chidamide-cisplatin-etoposide combination triggers immunogenic pyroptosis via the caspase-3/gasdermin E axis and activates adaptive immunity. This regimen represents a promising therapeutic strategy for relapsed diffuse large B-cell lymphoma warranting clinical investigation. Diffuse large B-cell lymphoma is a common blood cancer. Many patients are cured with standard chemotherapy, but others relapse and need new options. Our study tested whether combining a drug called chidamide with two chemotherapy drugs could help the immune system fight this cancer. We found this combination triggers a unique form of cancer cell death called pyroptosis, which alerts the immune system and attracts T cells to attack the tumor. Removing these T cells stopped the treatment from working, confirming their essential role. Our findings suggest this drug combination could become a new treatment for patients with relapsed lymphoma, offering more effective therapy by harnessing the body’s own immune system. Wu, Ye, Ran, Wang et al. investigate combining the HDAC inhibitor chidamide with cisplatin and etoposide in diffuse large B-cell lymphoma. They find that this activates caspase3/gasdermin E-mediated pyroptosis to remodel the tumor microenvironment and enhance CD8 + T cell infiltration, representing a promising immunotherapy strategy for relapsed disease.