Review Unpacks How Circular RNAs Drive Cancer Therapy Resistance via STAT3 Signaling Pathway

Cancer therapy resistance is a critical hurdle in effective oncology, leading to disease progression and poor patient outcomes. The STAT3 signaling pathway is a well-established central regulator promoting both cancer progression and resistance to treatment. Despite its importance as an anti-cancer target, direct STAT3 inhibitors lack clinical approval. This review addresses the emerging role of circular RNAs (circRNAs) as key modulators of STAT3 activity, highlighting a significant gap in understanding and targeting this resistance mechanism.

This comprehensive review synthesized current literature on the molecular functions of circular RNAs (circRNAs) in regulating cancer therapy resistance through the STAT3 signaling pathway. Researchers systematically discussed how circRNAs influence resistance to immunotherapy, chemotherapy, and radiotherapy across various malignancies. The review also explored the role of exosomal circRNAs in mediating STAT3-driven resistance via intercellular communication, drawing from a broad range of preclinical and mechanistic studies.

The review elucidated that circRNAs aberrantly stimulate or suppress cancer therapy resistance by diverse molecular mechanisms within the STAT3 pathway.

circRNAs function as protein recruiters, protein scaffolds, miRNA sponges, and even templates for peptide translation, all contributing to the modulation of STAT3 activity. Specifically, the circRNA/STAT3 axis was found to play a critical role in resistance to various therapeutic modalities, including immunotherapy, chemotherapy, and radiotherapy across a spectrum of cancers. The authors highlighted how exosomal circRNAs facilitate intercellular communication, thereby mediating STAT3-driven resistance in distant cells. This intricate regulatory network underscores the complexity of resistance mechanisms and points to circRNAs as versatile players in cancer biology.