Circular RNAs in NSCLC: Their Role in Tumorigenesis, Tumor Microenvironment Reshaping, and Response to Therapies

Lung cancer is the leading cause of cancer death worldwide. However, the molecular mechanisms involved in its development and response to therapies remain poorly understood. Previous studies have unraveled the pro- or anti-tumoral roles of circular RNAs (circRNAs) in numerous cancers. These mostly non-coding RNAs consist of a single-strand RNA forming a stable closed loop. CircRNA expression is often dysregulated in cancers, including lung cancer. An increasing number of studies have been published describing the role of circRNAs in lung tumor progression and/or resistance to therapies. Most of these studies have focused on how circRNAs impact cancer cells in a cell-autonomous manner, but less is known about the role of tumoral circRNAs in the crosstalk between cancer cells and cells from the tumor microenvironment (TME). In this review, focusing on non-small cell lung cancer (NSCLC), we provide a comprehensive and up-to-date analysis of the current knowledge in this emerging field. We highlight key molecular mechanisms by which tumor-derived circRNAs reshape the NSCLC tumor immune microenvironment. We also discuss recent findings showing their contributions to most NSCLC hallmarks, including those newly described in 2022, as well as their involvement in NSCLC's escape from therapies. All these studies clearly open avenues for translational applications of circRNAs in NSCLC, as either potential biomarkers or therapeutic targets, although current limitations clearly need to be overcome to translate circRNAs into the clinic.