Synergistic vulnerability of aggressive B-cell lymphoma to combined MCL-1 inhibition and CAR-T cell therapy

Abstract Aggressive B-cell lymphomas are often driven by MYC overexpression, which contributes to their rapid progression, therapeutic resistance, and poor prognosis. Although chimeric antigen receptor (CAR)-T cell therapy has shown impressive clinical benefits in treating B-cell lymphomas, resistance and disease relapse still occur in nearly half of patients who initially respond. In this study, we identify that drug-tolerant persister (DTP) cells and therapy-resistant lymphoma cells persist within a highly immunogenic tumor microenvironment (TME) that emerges following treatment with the MCL-1 inhibitor S63845. Mechanistic investigations reveal that MCL-1 inhibition suppresses MYC expression and activates the STAT1-interferon inflammatory signaling cascade, thereby enhancing cytotoxic T cell infiltration and reducing tumor-associated myeloid cells, both in vitro and in vivo. We further demonstrate that administering a sublethal dose of MCL-1i increases the immunogenicity of the TME and reactivates anti-tumor immune responses in mouse models. Importantly, we find that combining MCL-1i with CD19 CAR-T cells overcomes resistance to either monotherapy alone. Sequential administration-MCL-1i followed by CAR-T treatment-yields a marked improvement in therapeutic outcomes, leading to near-complete eradication of MYC-driven lymphoma in vivo. Overall, our findings support a synergistic dual-targeting strategy that addresses both tumor-intrinsic survival mechanisms and the immunosuppressive TME. This combinatorial “one-two punch” approach holds strong potential for eliminating minimal residual disease, preventing relapse, and achieving sustained clinical remissions in aggressive B-cell lymphomas.