SRP312327 PRJNA717750 GSE169711 TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observed that expression of telomerase reverse transcriptase (TERT) is closely associated with immune-suppressive signatures. We demonstrated that TERT can activate a subclass of endogenous retroviruses (ERVs) to form double-stranded RNAs (dsRNAs), which were sensed by the RIG-1/MDA5-MAVS signalling pathway and triggered interferon signalling in cancer cells. Furthermore, we showed that TERT-induced ERVs/interferon signalling stimulated the expression of chemokines, including CXCL10, which induced suppressed T cell infiltration with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERVs/interferon signalling contributes to immune suppression in tumours. Overall design: mRNA profiles of U2OS cells transfected with pcDNA3.1-TERT-WT, pcDNA3.1-TERT-K626A or empty vector using Lipofectamine 3000 according to the manufacturer's instructions for 48 h. GSE169711 pubmed 35107856 parent_bioproject PRJNA717744