Disrupting immune silence: Noncoding RNAs targeting the programmed cell death protein 1/programmed cell death ligand 1 axis in tumor immunity.

PD-1 and PD-L1 are programmed cell death proteins and ligands that form a key axis of immune checkpoints that tumors use to escape immune surveillance. Although immune checkpoint inhibitors that activate this pathway have revolutionized the treatment of cancer, resistance and unpredictable responses to a patient are still significant issues. There is growing evidence that noncoding RNAs (ncRNAs) such as microRNAs, long noncoding RNAs, and circular RNAs are key regulators of PD-1/PD-L1 signaling. These ncRNAs control the PD-L1 expression by directing its mRNA and indirectly maintaining the upstream signaling processes, consequently influencing tumor progression, immune cell activity, and drug responses. This review, based on existing research on the mechanistic functions of ncRNAs in PD-1/PD-L1-based immune suppression, discusses the possibility of using ncRNAs as biomarkers to predict immunotherapy response and as new therapies. We also address opportunities in the field of translation, such as ncRNA-based interventions and combinations with checkpoint blockade, and the challenges, which require resolution to move to the clinical practice. The combination of ncRNA biology and tumor immunology has potential applications in the area of precision immunotherapy and the creation of more meaningful treatment tools against malignancies that are resistant to treatment. SIGNIFICANCE STATEMENT: The current review outlines the regulatory functions of noncoding RNAs in the programmed cell death protein 1/programmed cell death ligand 1 immune checkpoint and highlights their role in tumor immune evasion and therapeutic responses regulation. With an interwoven method of mechanistic understanding and translational approaches, this study outlines noncoding RNAs as potential biomarkers and therapeutic targets and provide new approaches to increment the activity of checkpoint blocks and improve precision cancer immunotherapy.