Reprogramming CAR with Cytokine Signaling Increases the Efficacy of CAR T-cell Therapy in Solid Tumor Treatment and Confers Sustained Immune Memory.

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in hematologic malignancies but remains limited in solid tumors because of the immunosuppressive microenvironment, tumor heterogeneity, poor immune cell infiltration, and progressive T-cell dysfunction. Because cytokine costimulation is critical for maintaining T-cell fitness, we developed a modular engineering strategy, distinct from previous approaches based on the direct insertion of large cytokine receptor fragments, in which the intracellular CAR signaling domain was reconstructed to incorporate compact IL2/IL15 receptor-derived activation motifs, thereby enabling antigen-dependent coactivation while preserving the overall architecture of the parental CAR. Through systematic screening, we identified S71 as the optimal construct, with significantly greater antitumor activity than other mutants across multiple solid and hematologic tumor targets. Mechanistically, S71 rewired CAR signaling and reprogrammed tumor-induced metabolic responses through a self-sustaining mechanism, improving mitochondrial function and supporting durable T-cell activity. Functionally, S71 promoted enhanced persistence and robust immune memory responses against solid tumors. These findings demonstrate that the modular integration of cytokine signaling motifs into CAR intracellular domains can improve CAR T-cell fitness and antitumor efficacy, and they establish S71 as a promising strategy for overcoming barriers to CAR T-cell therapy in solid tumors.