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.