Beyond CD30: Dual‐Targeting of Malignant and Regulatory T Cells by Brentuximab Vedotin Remodels the Lymphoma Microenvironment and Overcomes Resistance via BCL2 Inhibition in Mycosis Fungoides

ABSTRACT Mycosis fungoides (MF), the most common subtype of cutaneous T cell lymphoma (CTCL), has a poor prognosis in advanced stages. Brentuximab vedotin (BV), a CD30‐targeting antigen‐drug conjugate approved for CD30 + MF following prior systemic treatment, still exhibits resistance with unclarified mechanisms. With single‐cell RNA analysis on 13 paired tumor samples from 6 CD30 + MF patients, we revealed that BV‐induced immunogenic cell death (ICD) in both CD30 + and CD30 − malignant T cells while specifically enhanced interferon‐α (IFNα) and IFNγ responses in CD30 − subsets. BV also directly targeted CD30 + tumor‐infiltrating regulatory T cells (TI‐Tregs), and activated anti‐tumor immunity mediated by dendritic cells and CD8 + T cells. The treatment responses and mechanistic insights were validated using seven CTCL cell lines. Resistance arose from upregulated drug efflux transporters and impaired endosomal processing in CD30 + malignant T cells, while CD30 − tumor cells showed blunted IFNα and IFNγ responses. Anti‐apoptotic BCL2 was upregulated in all tumor cells from nonresponsive lesions, especially in CD30 − subsets. We further confirmed a potent synergy between BV and BCL2 inhibitors in tumor cell lines, indicating a promising strategy to overcome resistance in CTCL.