LISS enables immune evasion of colorectal cancers irrespective of MSI status.

Despite being hailed as a significant advancement in cancer treatment, immune checkpoint blockade (ICB) has not yielded favorable outcomes in colorectal cancer, both in approximately 85% of cases characterized by microsatellite stability (MSS) and approximately 50% of microsatellite instability (MSI) cases. How ICB efficiency in colorectal cancer treatment can be improved remains unclear. Here, we identify a new immunoregulatory long non-coding RNA (lncRNA) gene named lncRNA of IFN-γ-signaling suppressor (LISS). LISS expression is increased in colorectal cancers and is linked to poor prognosis, as well as a high CD8+ score. Functional studies reveal that LISS impairs T cell-mediated cytotoxicity, regardless of MSS/MSI status. Mechanistically, LISS interacts directly with the kinase regulatory domain in calmodulin-dependent kinase (CamK)IIγ through a microdomain containing two independent RNA stem-loops. This interaction prevents the binding and phosphorylation of its substrate signal transducer and activator of transcription1 (STAT1) at serine(S)727, a modification necessary for optimal activation of STAT1 and the subsequent major histocompatibility complex I (MHC-I) gene expression. Analysis of human colorectal cancer samples reveals significant inverse correlations between LISS and pS-STAT1 or MHC-I. The knock-in of LISS in intestinal epithelium promotes adenoma development in Apcmin/+ mice. LISS antisense oligonucleotide (ASO)-based therapies enhance the responses of both MSS and MSI colorectal cancers to ICB in vivo, mainly by restoring MHC-I expression. Therefore, we have identified the previously uncharacterized lncRNA LISS to be a regulator of T cell immunity. Targeting it may be an effective therapeutic strategy to improve ICB in colorectal cancers with varying MSI characteristics.