Advancing the next generation of cancer treatment with circular RNAs in CAR-T cell therapy.

Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies. However, its effectiveness against solid tumors remains constrained by challenges such as T-cell exhaustion, limited persistence, and off-target effects. These challenges highlight critical gaps in current CAR-T cell therapeutic strategies, particularly for solid tumor applications. Circular RNAs (circRNAs) represent a transformative class of non-coding RNAs, known for their exceptional stability and precise regulatory functions, positioning them as promising candidates for enhancing next-generation CAR-T cell therapies. Notably, circRNAs can bridge the gap between preclinical research and clinical application by offering innovative solutions to overcome technical hurdles and improve therapeutic outcomes. Despite their potential, circRNAs remain underexplored in clinical application of CAR-T cell therapies for solid tumors, presenting a significant opportunity for innovation. The mechanisms through which circRNAs modulate CAR-T cell exhaustion, persistence, and tumor specificity are not yet fully understood, and technical challenges, such as achieving efficient and targeted circRNA delivery, which still need to be addressed. This review highlights the importance of integrating circRNAs into CAR-T cell therapy to enhance specificity, minimize off-target effects, and improve therapeutic durability. By emphasizing the innovative potential of circRNAs and identifying key research gaps, this review provides a roadmap for advancing CAR-T cell therapy and setting the stage for the next generation of personalized cancer treatments.