Therapeutic resistance in aggressive B-cell lymphoma is overcome through the reciprocal enhanced efficacy by CDK9 inhibitors and CAR-T cells

Abstract Although both CDK9 inhibitors and chimeric antigen receptor (CAR)-T cells have shown significant clinical promise in treating B-cell lymphomas, therapeutic resistance continues to pose a major challenge. In this study, we show that while CDK9 inhibitor (CDK9i) treatment efficiently eliminates the majority of lymphoma cells, a subset of drug-tolerant persister (DTP) and resistant cells survives within a CDK9i-induced, highly immunogenic tumor microenvironment (TME). Mechanistically, CDK9 inhibition reprograms lymphoma cells toward a more immunogenic phenotype through activation of the interferon (IFN)-driven inflammatory pathway, which enhances cytotoxic T cell infiltration and strengthens CAR-T cell efficacy in both in vitro and in vivo models of aggressive B-cell lymphoma. Importantly, CDK9i and CD19-directed CAR-T cells exhibit reciprocal sensitization, each overcoming resistance to the other. Sequential treatment-with CDK9i preceding CAR-T infusion-markedly improves therapeutic outcomes and durability, achieving near-complete lymphoma eradication in vivo. Collectively, these results underscore a synergistic dual-targeting approach that tackles both tumor-intrinsic survival mechanisms and the immunosuppressive TME. This combinatorial “one-two punch” strategy holds strong potential to more effectively eliminate minimal residual disease (MRD), prevent relapse, and drive complete and durable remissions in aggressive B-cell lymphomas.