Combating CD24 to overcome CD19 CAR-T resistance via induction of innate and adaptive immunity in B-cell malignancies.

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.