Long non-coding RNAs in colorectal cancer: shaping the tumour microenvironment and advancing precision oncology

A new frontier in cancer research is emerging with the exploration of 'dark DNA': the non-coding regions of the genome now recognized as essential regulators of cancer biology. Long non-coding RNAs (lncRNAs) have been increasingly acknowledged as key regulators in cancer, having crucial roles in the modulation of intracellular processes as well as in intercellular communication. These roles emphasize the importance of lncRNAs in influencing the tumour microenvironment (TME), a complex and dynamic network that contributes to cancer progression, metastasis and resistance to therapy. In this Review, we explore how lncRNAs regulate the colorectal cancer (CRC) microenvironment, focusing on their mechanisms of action and their effect on critical TME components, including immune cells, cancer-associated fibroblasts and angiogenesis. We explore the dual roles of lncRNAs as oncogenes or tumour suppressors, their involvement in immune modulation, vascular remodelling and extracellular matrix dynamics. Our comprehensive analysis elucidates the molecular pathways, identifies potential biomarkers for patient stratification and proposes new therapeutic strategies to regulate the CRC TME and prevent disease progression and resistance. Ultimately, this Review contributes to a deeper understanding of the intricate lncRNA-TME interplay and underscores their emerging relevance in clinical applications, paving the way for innovations in precision oncology.