MicroRNA-Orchestrated Modulation of CAR-T Cells: Overcoming Functional Barriers Toward Next-Generation Immunotherapy

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment outcomes in hematologic cancers, yet its impact on solid tumors remains limited due to barriers such as antigen heterogeneity, functional exhaustion, immunosuppressive microenvironments, and inefficient tumor infiltration. Recent studies identify microRNAs (miRNAs) as central regulators of T-cell activation, persistence, differentiation, and metabolic adaptation, functioning as post-transcriptional rheostats rather than simple on/off switches. By modulating checkpoint pathways, chemokine responsiveness, and resistance to hypoxic stress, specific miRNAs-including miR-17~92, miR-155, miR-210, and miR-21-have demonstrated potential to enhance CAR-T performance across multiple functional axes. Here, we synthesize evidence from mechanistic research, preclinical studies, and early clinical observations on emerging delivery strategies such as synthetic oligonucleotide inhibitors/mimics, vectorized circuits, circular-RNA systems, and exosome-based carriers. Together, these findings suggest that miRNA engineering offers a versatile platform for next-generation CAR-T design, enabling multi-layered functional reprogramming while underscoring the need for rigorous clinical validation in solid tumor settings.