Xiangao Huang

CD24 is highly expressed in aggressive B-cell malignancies and represents a novel immunologic vulnerability to overcome resistance to CD19 chimeric antigen receptor T-cell (CAR-T) therapy. We developed a CD24 × CD3 bispecific antibody (CD24 BsAb) and CXCR3-armed CD24 CAR-T cells, both exhibiting potent antitumor activity in lymphoma and leukemia models. CD24 BsAb and CD24 CAR-T overcome CD19 CAR-T resistance driven by antigen loss and apoptosis defects in vitro and in vivo. Beyond direct cytotoxicity, CD24-targeted T cells reprogram macrophages toward an M1-like phenotype and enhance phagocytic clearance. We further engineered a dual-specific, dual-functional CD19 CAR-T that secretes a CD24 bispecific T-cell engager (CD24 BiTE), enabling simultaneous targeting of CD19 and CD24 to address tumor heterogeneity and achieve superior efficacy. Collectively, our study demonstrates that CD24-directed adoptive T-cell therapies are warranted for B-cell malignancies through robust induction of both innate and adaptive immune responses.

Resistance to Bruton’s tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies. Here, we identify chromatin remodeler BRG1-mediated suppression of ferroptosis as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL), in which aberrant BRG1-dependent transcription program protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through regulation of both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates atypical mitochondrial complex I subunit NDUFA4L2. Increased NDUFA4L2 restricts cellular respiration, preemptively limiting mitochondrial ROS generation and activating AMPK signaling, together reducing susceptibility to lipid peroxidation and ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, our study establishes BRG1 as a central regulator of BTKi resistance and provides a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.