Rewiring cellular immunotherapy: From CAR evolution to circuit innovations across diseases

Chimeric antigen receptor (CAR)-based immunotherapy has evolved from early linear receptor designs into increasingly sophisticated biological signal processing systems. While conventional CAR-T cell therapies have achieved remarkable clinical success, particularly in hematologic malignancies, their broader application is constrained by limited scalability, manufacturing complexity, and treatment-related toxicities. These challenges have driven the expansion of CAR engineering beyond T cells to alternative immune cell types, including natural killer (NK) cells and macrophages, as well as the diversification of genetic delivery and control strategies. Concurrently, advances in synthetic biology have reframed CARs not merely as static receptors but as programmable immune circuits capable of integrating multiple inputs, executing logical operations, and generating context-dependent outputs. Such circuit-based designs enable precise regulation of immune activation, improved discrimination between tumor and healthy tissues, and enhanced functional persistence within heterogeneous and immunosuppressive microenvironments. In this review, we conceptualize CAR-based immunotherapy as a form of biological signal processing and systematically trace its transition from linear CAR architectures to programmable immune circuits. We summarize engineering strategies for both ex vivo and in situ reprogramming of immune cells, compare viral and nonviral gene delivery platforms, and discuss key design principles underlying circuit CARs across different disease contexts.