Next-Generation CAR-T Cell Therapy: From Modular Design to Clinical Expansion

Chimeric antigen receptor (CAR)-T cell therapy has emerged as a groundbreaking treatment for cancer. After decades of research, it is now being actively explored for a broader range of immune-mediated diseases, particularly cancer and autoimmune disorders. Significant progress has been made in both understanding technological advancements and addressing the intrinsic limitations of this engineered cellular therapy. However, the clinical efficacy and safety of CAR-T cells remain influenced by several factors, including the immunosuppressive tumour microenvironment (TME), the continuous mutational evolution of tumour cells, the prohibitive cost of production limiting accessibility, and the immune-related toxicities associated with biologic treatments. Given these substantial challenges, a paradigm shift is urgently needed - from conceptualizing CAR-T cells solely as "engineered immune cells" to recognizing them as "programmable intelligent systems." This review proposes a dynamic immune engineering framework, advocating that the next generation of CAR-T cells be conceived as programmable immune systems capable of sensing, responding to, and self-regulating immune responses. This evolving approach positions dynamic immune regulation as the core principle underlying immune system function. Ultimately, this review aims to provide a conceptual and theoretical foundation for the development of next-generation CAR-T therapies that are not only highly effective but also cost-efficient and globally accessible.