A TERRA-NONO axis drives fibroblast reprogramming in cancer.

The molecular mechanisms linking chromosome homeostasis to fibroblast reprogramming into cancer-associated fibroblasts (CAFs) remain poorly understood. Here, we identify a clinically relevant, telomere-associated nuclear pathway driving CAF activation across multiple human cancers. The long noncoding RNA TERRA is consistently elevated in CAFs from skin, lung, and breast tumors. We show that the androgen receptor (AR) represses TERRA transcription through subtelomeric binding, and its loss enables TERRA up-regulation and interaction with the RNA binding protein NONO. This interaction forms a CAF-specific nuclear complex that reprograms gene expression. Mechanistically, NONO is directly recruited to and binds the promoters of key CAF effector genes, where it regulates their transcription in a TERRA-dependent manner. Disrupting the TERRA-NONO axis, via TERRA silencing or pharmacologic NONO inhibition, reverses CAF activation and suppresses tumor-stroma interactions in vitro and in vivo, highlighting its therapeutic potential.