lncRNAs in Tumor Microenvironment Drive Cancer Progression

The tumor microenvironment (TME) is a highly complex and adaptive network where tumor cells interact with immune cells, stromal cells, extracellular matrix (ECM), cytokines, and signaling molecules. A crucial player in this environment is long non-coding RNAs (lncRNAs)—non-protein-coding transcripts over 200 nucleotides in length—that profoundly influence the behavior of both cancerous and non-cancerous cells in the TME.

lncRNAs and TME Dynamics

Molecular regulators within the tumor microenvironment are emerging as critical influencers of gene expression, shaping processes such as immune evasion, angiogenesis, metastasis, and metabolic reprogramming. These elements function at transcriptional, post-transcriptional, and epigenetic levels, affecting tumor progression both directly and indirectly.

They promote cancer cell proliferation, alter stromal cell function, and assist in creating a pro-tumorigenic environment by facilitating the transformation of normal fibroblasts into tumor-associated fibroblasts (TAFs). This transformation supports tumor growth, enhances invasion, and contributes to therapy resistance.

lncRNAs in Tumor-Associated Fibroblasts

Within TAFs, lncRNAs like MALAT1 and DNM3OS are highly expressed, playing vital roles in promoting cancer invasiveness and radiation resistance. In oral squamous cell carcinoma, the lncRNA LOC100506114 is upregulated, aiding in TAF transformation and accelerating tumor progression.

lncRNAs and Angiogenesis

Angiogenesis—the formation of new blood vessels—is crucial for tumor survival. lncRNAs such as PVT1 in gastric cancer and NR2F1-AS1 in breast cancer enhance angiogenic signaling by upregulating VEGFA and endothelial markers. Their inhibition has shown to reduce vascularization and increase chemotherapy efficacy, presenting them as valuable therapeutic targets.

lncRNAs and Immune Modulation in TME

lncRNAs also manipulate immune cells in the TME to evade detection. For instance, in breast cancer, HISLA is transferred via exosomes from tumor-associated macrophages to cancer cells, enhancing glycolysis and chemoresistance. Others like NEAT1 downregulate immune checkpoints, further weakening immune surveillance.

Exosomal lncRNAs as Communication Tools

Exosomal lncRNAs serve as messengers between tumor and stromal cells. The lncRNA CRNDE, transmitted via exosomes from macrophages to gastric cancer cells, promotes chemotherapy resistance by degrading the tumor suppressor gene PTEN. These exosomal transfers reveal potential intervention points for halting tumor progression.

Clinical Implications and Therapeutic Opportunities

lncRNAs in the tumor microenvironment are gaining attention as non-invasive biomarkers for early cancer detection due to their stability and tissue-specific expression. They are also being explored as targets for new cancer therapies using technologies like RNA interference, antisense oligonucleotides, and CRISPR. Challenges remain in delivery and specificity, but emerging nanotechnologies may soon overcome these barriers.

Conclusion

The strategic targeting of lncRNAs in the tumor microenvironment offers a promising path to disrupt tumor-supportive mechanisms and combat drug resistance. With their expanding relevance in oncology, lncRNAs represent not only a deeper understanding of cancer biology but also a frontier for innovative diagnostics and treatments.

For more information: Beylerli, O., et al. (2025). Tumor Microenvironment Dynamics: The Regulatory Influence of Long Non-coding RNAs. Gene Expression. doi.org/10.14218/ge.2024.00069.