CAR-engineered cell therapy in severe asthma: a target–function–patient framework for translational decision-making

Severe asthma is increasingly managed with endotype-guided biologics, yet a clinically important subgroup remains corticosteroid-dependent, repeatedly exacerbating, or unable to achieve durable multidomain remission. Chimeric antigen receptor (CAR)-engineered cells offer a qualitatively different therapeutic logic: recognition of a cellular compartment can be coupled to selective depletion, localized regulation, or payload delivery, potentially enabling finite immune reprogramming rather than continuous mediator blockade. This Review asks under what conditions that added biological risk could be justified in asthma. We classify evidence into four proximity tiers—direct asthma preclinical evidence, patient-derived ex vivo or disease-adjacent preclinical evidence, human clinical evidence in other immune-mediated diseases, and broader platform evidence—and use this hierarchy to support explicit go/no-go judgments rather than catalogue constructs. Direct asthma studies support lung-directed CAR-regulatory T cells, IL-5/IL-5Rα-directed cytotoxic strategies, multifunctional type 2 pathway control, and allergen-specific CAR-Tregs; clinical efficacy in asthma has not been established. We propose a target–function–patient framework organized around four mandatory gates: clinical necessity, mechanistic coherence, targetability, and reversibility planning. Targets should be prioritized by pathogenic necessity and physiological dispensability; the cellular chassis and receptor program should be chosen according to the required biological function; and treatment should be restricted to biomarker-defined patients whose residual disease burden justifies living-cell therapy. In asthma, maximal cytotoxicity and indefinite persistence are not default virtues. The most plausible initial role is a narrow, biologic-refractory population in whom a controllable, mechanistically verified intervention can durably interrupt a disease-maintaining cellular circuit while preserving host defense and tissue repair.