Advancements and challenges of R-loops in cancers: Biological insights and future directions

R-loops involve in various biological processes under human normal physiological conditions. Disruption of R-loops can lead to disease onset and affect the progression of illnesses, particularly in cancers. Herein, we summarized and discussed the regulative networks, phenotypes and future directions of R-loops in cancers. In this review, we highlighted the following insights: (1) R-loops significantly influence cancer development, progression and treatment efficiency by regulating key genes, such as PARPs, BRCA1/2, sex hormone receptors, DHX9, and TOP1. (2) Currently, the ATM, ATR, cGAS/STING, and noncanonical pathways are the main pathways that involve in the regulatory network of R-loops in cancer. (3) Cancer biology can be modulated by R-loops-regulated phenotypes, including RNA methylation, DNA and histone methylation, oxidative stress, immune and inflammation regulation, and senescence. (4) Regulation of R-loops induces kinds of drug resistance in various cancers, suggesting that targeting R-loops maybe a promising way to overcome treatment resistance. (5) The role of R-loops in tumorigenesis remains controversial, and senescence may be a crucial research direction to unravel the mechanism of R-loop-induced tumorigenesis. Looking forward, further studies are needed to elucidate the specific mechanisms of R-loops in cancer, laying the groundwork for preclinical and clinical research.