# Synthetic lethality of MCL-1 inhibition and CAR-T therapy in aggressive B-cell lymphoma

## TL;DR

Combining MCL-1 inhibition with CAR-T therapy effectively treats aggressive B-cell lymphoma by targeting both cancer cells and the tumor environment.

## Contribution

The study introduces a synergistic combination of MCL-1 inhibition and CAR-T therapy to overcome resistance in B-cell lymphoma.

## Key findings

- MCL-1 inhibition activates anti-tumor immune responses and reduces immunosuppressive cells in the tumor microenvironment.
- Combining MCL-1i with CD19 CAR-T cells nearly eradicates MYC-driven lymphoma in murine models.
- The dual therapy overcomes resistance to single-agent treatments and prevents disease relapse.

## Abstract

Aggressive B-cell lymphomas, driven by MYC overexpression, exhibit rapid progression, resistance to therapies, and poor survival. While chimeric antigen receptor (CAR)-engineered T cells have demonstrated remarkable clinical efficacy in B-cell lymphomas, nearly half of patients who initially respond to CAR-T therapy eventually develop resistance and disease progression. In this study, we report the presence of residual drug-tolerant persister (DTP) and resistant lymphoma cells remaining within a highly immunogenic tumor microenvironment (TME) induced by the MCL-1 inhibitor (MCL-1i) S63845. MCL-1 inhibition downregulates MYC and activates the STAT1-interferon inflammatory pathway, promoting cytotoxic T-cell infiltration with reduced tumor-associated myeloid cells both in vitro and in vivo. Sublethal dose of the MCL-1i enhances TME immunogenicity and reawakens anti-tumor immune responses in murine models. We show that MCL-1i and CD19-targeted CAR-T cells reciprocally overcome resistance to each single-agent therapy, and combining MCL-1i with CD19 CAR-T cells significantly improves treatment efficacy, resulting in near-complete eradication of MYC-driven lymphoma in vivo. Together, these findings highlight a synergistic, dual-pronged therapeutic strategy targeting both tumor-intrinsic survival pathways and the immunosuppressive TME. This combinatorial one-two-punch approach offers a promising path to eliminate DTP and residual disease, prevent relapse and pave the way for deep clinical remissions in aggressive B-cell lymphomas.