Designing immunity with cytokines: A logic-based framework for programmable CAR therapies

Adoptive cellular immunotherapy has transformed cancer care, with chimeric antigen receptor (CAR) T cells achieving unprecedented remission in hematologic malignancies. Yet solid tumor translation remains limited by antigen escape, hostile microenvironments, and life-threatening toxicities. Cytokines and chemokines are central to these barriers, shaping trafficking, persistence, and toxicity in ways that demand engineered solutions. This review introduces the first unified five-layer framework—Recognition, Navigation, Safety, Persistence, and Translation—that organizes CAR engineering through cytokine and chemokine logic. Innovations include dual-target and logic-gated CARs to counter heterogeneity, hypoxia- and chemokine-responsive circuits to enhance infiltration, inducible safety switches to mitigate IL-6/IL-1β–driven cytokine storm, and IL-7/IL-15 support to extend persistence. Beyond T cells, CAR logic is now ported into NK cells and macrophages, complementing adaptive memory with innate cytotoxicity and stromal remodeling, while iPSC-derived effectors offer scalable, standardized production. Together, these advances reframe cellular immunotherapy as a cytokine-guided, programmable immune ecosystem, providing a conceptual roadmap for therapies engineered not only for potency but also for safety, durability, and broad clinical integration.