Telomeres rule immunity in brain tumors

Microglia and other immune cells in glioblastoma foster a pro-tumorigenic environment that limits therapeutic efficacy. In a zebrafish model, brain tumors are heavily infiltrated by immune cells overexpressing RIG-I-like RNA-sensing components. This model is marked by chromosome instability from the Alternative Lengthening of Telomeres (ALT) pathway, which produces aberrant RNAs, including TERRA. We found that TERRA interacts with MDA5, and that loss of MDA5 or TERRA reduces macrophage infiltration, tumor cell proliferation, and improves zebrafish survival. Single-cell RNA-Seq further reveals that TERRA knock down triggers an increase of anti-tumoral immunity. Together, these findings suggest that targeting TERRA-driven RNA sensing may restrain tumor growth and reprogram the immune microenvironment in brain tumors.