Exosomal microRNAs as promising indicators of chemoresistance in lung cancer

To the Editor, Despite the decades of advancements in therapeutics, lung cancer remains the deadliest cancer worldwide, with an overall survival rate of only 10–20%, highlighting the urgent need for early detection strategies to overcome the growing burden of chemoresistance[1]. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, which makes up nearly 85% of cases. A major obstacle to a better prognosis is resistance to platinum-based chemotherapy, which often causes treatment failure, cancer recurrence, and poor survival. Recent evidence highlighted the role of epigenetic changes, including DNA methylation, histone modification, chromatin remodeling, and non-coding RNA regulation in chemoresistance by altering gene expression and signaling pathways[2]. Long non-coding RNAs (lncRNAs) further contribute by reshaping chromatin structure and interacting with microRNAs (miRNAs), often transported between tumor cells by exosomes[3]. This suggests that exosomes are not only carriers of oncogenic signals but also active contributors to treatment failure. This manuscript complies with TITAN guidelines[4]. Building on this knowledge, circulating exosomal miRNAs are emerging as a promising non-invasive biomarker for the early prediction of chemoresistance. Specific miRNAs, such as miR-21-5p and miR-126-3p, have been elevated in chemoresistant NSCLC patients and correlate with poor response to platinum-based therapy[5]. Regular monitoring of these miRNAs could enable clinicians to anticipate emerging resistance, modify treatment strategies proactively, and improve patient outcomes. Although exosomal miRNAs show great promise for predicting chemoresistance, they are not yet part of routine NSCLC care. This is largely due to the lack of standardized tests; long-term monitoring has not been fully studied, and patient differences make results unpredictable. Bridging these gaps is key to turning these molecular discoveries into practical tools that can guide treatment. Addressing these barriers, such as variability in exosome content, differences in isolation and quantification methods, and patient heterogeneity, is essential before exosomal miRNA profiling can be reliably used in clinical practice[3,5]. In conclusion, we believe that integrating exosomal miRNA signatures with existing knowledge of epigenetic processes and lncRNA-driven mechanisms offers a proactive approach to overcoming chemoresistance in NSCLC. By linking molecular discoveries with bedside care, this strategy holds the potential to enhance survival and improve quality of life for lung cancer patients. Future studies should focus on validating exosomal miRNA signatures in large, multi-center studies to enable their reliable integration into clinical practice.