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<p>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 (<i>LISS</i>). <i>LISS</i> expression is increased in colorectal cancers and is linked to poor prognosis, as well as a high CD8+ score. Functional studies reveal that <i>LISS</i> impairs T cell-mediated cytotoxicity, regardless of MSS/MSI status. Mechanistically, <i>LISS</i> 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 <i>LISS</i> and pS-STAT1 or MHC-I. The knock-in of <i>LISS</i> in intestinal epithelium promotes adenoma development in <i>Apc</i><sup><i>min/+</i></sup> mice. <i>LISS</i> 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 <i>LISS</i> 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.</p>

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LISS enables immune evasion of colorectal cancers irrespective of MSI status

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • Qingyu Lin,
  • Xingwen Wang,
  • Weixu Zhao,
  • Shiying Song,
  • Yi Zhang,
  • Jiangwen Ma,
  • Tianyu Li,
  • Yuhan Wei,
  • Minqiao Lu,
  • Guixue Hou,
  • Meiqi Wang,
  • Hao Liu,
  • Shanliang Zheng,
  • Olga Burenina,
  • Zhiyuan Xiang,
  • Li Li,
  • Jiaqi Zhu,
  • Ying Hu

摘要

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.