CAR-T-drug conjugate against solid tumor [RNA-seq/BCR-seq]

Chimeric antigen receptor (CAR)-T cell therapy has been clinically successful in hematologic malignancies but faces challenges in solid tumors, including limited infiltration, immunosuppressive microenvironments and antigen heterogeneity. While combining CAR-T cell therapy with chemotherapy can enhance antitumor activity, this often leads to substantial systemic toxicity. Here we show that CAR-T-drug conjugate (CAR-T-D-C), generated through click chemistry-mediated conjugation of cytotoxic payloads to antigen-specific CAR-T cells, enable localized drug delivery while preserving CAR-T cell function. CAR-T-D-Cs incorporating different CAR-T cell binders exhibit robust antitumor activity across multiple human xenografts and syngeneic tumor models. Spatial transcriptomic analyses reveal enhanced intratumoral CAR-T infiltration and activation following CAR-T-D-C treatment . Compared with conventional CAR-T therapy, CAR-T-D-C enhances immune cell infiltration, augments effector functions, promotes antigen spreading and amplifies systemic anti-tumor immunity. CAR-T-D-C represents a versatile therapeutic platform that combines the specificity of cellular immunotherapy with the potency of small-molecule therapeutics for treatment of solid tumors.