A molecular pathway that simultaneously fuels cancer stem cell formation and helps tumors hide from immune surveillance could revolutionize treatment approaches for the deadliest form of breast cancer. This discovery challenges the conventional view that stemness and immune evasion operate through separate mechanisms.
Researchers identified ISG20, an RNA-degrading enzyme, as a central orchestrator of triple-negative breast cancer (TNBC) aggressiveness. Under low-oxygen conditions common in tumors, the hypoxia-inducible factor HIF-1 activates ISG20 expression. This enzyme then selectively destroys specific messenger RNAs: it degrades RHOBTB3 mRNA, which amplifies HIF-1α protein levels and activates NANOG signaling pathways that generate cancer stem cells capable of seeding metastases. Simultaneously, ISG20 destroys STAT1 and IRF1 mRNAs, crippling the tumor's ability to produce CXCL10, a chemical signal that normally recruits cancer-fighting CD8+ T cells and natural killer cells.
This dual mechanism represents a sophisticated evolutionary strategy where cancer cells use one enzyme to both enhance their regenerative capacity and evade immune destruction. The finding is particularly significant for TNBC, which lacks targeted therapy options and has the highest mortality rates among breast cancers. When researchers silenced ISG20 in mouse models, tumors became significantly more responsive to PD-1 checkpoint inhibitor immunotherapy. This suggests ISG20 inhibitors combined with existing immunotherapies could transform outcomes for patients facing this aggressive cancer subtype, potentially converting immunotherapy-resistant tumors into responsive ones.