Structure-Function Insights into Immune Receptors Drive Innovation in CAR-T Cell Therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as the most transformative cellular immunotherapy modality, with its evolutionary trajectory intrinsically coupled to advances in immune receptor structure-function paradigms. Recent technological breakthroughs have yielded unprecedented mechanistic insights into immune receptors. Cryo-electron microscopy, single-cell omics, and structural biology have revealed the molecular architecture and functional dynamics of key receptors, including T-cell receptors (TCRs) and B-cell receptors (BCRs). This comprehensive review systematically integrates the latest discoveries in immune receptor structure-function relationships, emphasizing the mechanistic underpinnings of receptor diversity generation, signal transduction networks, and their direct translational impact on CAR-T therapeutic optimization. We critically examine the innovative design principles governing fourth-generation CAR-T cells, delineate breakthrough strategies for overcoming solid tumor immunoresistance, and analyze the synergistic potential of CAR-T and TCR-T technological convergence. Particular attention is devoted to elucidating how fundamental immune receptor research can be harnessed to address the tripartite challenges of safety, efficacy, and persistence that currently constrain CAR-T clinical applications. This review establishes a mechanistic framework for developing next-generation CAR-T technologies grounded in immune receptor biology and provides strategic insights for accelerating cellular immunotherapy clinical translation.