ncRNA-driven regulation of PD-L1 in breast cancer: mechanisms of immune escape and therapeutic opportunities.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule important in tumor immune evasion acting primarily by inhibiting T cell activation. In breast cancer, PD-L1 is frequently abnormally expressed and associated with tumor progression, metastasis, and poor prognosis. Recent studies have revealed that non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are important post-transcriptional regulators of PD-L1. ncRNAs regulate PD-L1 expression through multiple mechanisms, including direct binding to PD-L1 mRNA 3' UTR, acting as competing endogenous RNAs (ceRNAs), altering transcription factor activity, and altering epigenetic modifications. Dysregulation of ncRNAs not only impact PD-L1-mediated immune escape (i.e., cancer immune evasion), but can also remodel the tumor microenvironment (TME) through impact on immune cell infiltration and activity, and alterations to cytokine production. This review provides an overview of current understanding of ncRNAs regulating PD-L1 in breast cancer, specifically their molecular mechanisms, therapeutic potential, and clinical relevance as biomarkers and/or therapeutic targets. The broad ncRNA-PD-L1 regulatory network is complex, and discoveries in this field may create novel avenues for precision immunotherapy and combination strategies in treating breast cancer.