Immune checkpoint blockade (ICB) therapy is widely used in the clinical treatment of various solid tumors and has achieved favorable and durable efficacy. Colorectal cancer (CRC), ranking as the third most common cancer globally and the second leading cause of cancer-related mortality, exhibits a low response rate to ICB. Notably, microsatellite stable (MSS) patients, who account for approximately 85% of all CRC cases, show a response rate of merely 5–10%. How to improve ICB efficacy in CRC remains an urgent clinical challenge.
On May 26, 2026, Professor Hu Ying's research group from the School of Life Science and Technology, Harbin Institute of Technology, published a research article in Signal Transduction and Targeted Therapy (STTT) entitled LISS enables immune evasion of colorectal cancers irrespective of MSI status. This study elucidates the immune tolerance mechanism of CRC, including MSS-type tumors, from the perspective of long non-coding RNAs (lncRNAs), providing a novel therapeutic target for enhancing ICB efficacy.
The team screened genes associated with prognosis and immune infiltration in colorectal cancer patients using the TCGA database and identified a lncRNA gene with potential pro-tumorigenic activity, which they named LISS (IFN-γ-signaling suppressor). Using a spontaneous intestinal cancer mouse model with LISS-specific knock-in in intestinal epithelial cells, they demonstrated that LISS promotes tumorigenesis. Mouse subcutaneous colorectal cancer tumor models showed that this gene functions in both microsatellite instability (MSI) and MSS-type CRC. Moreover, after inhibiting CD8+ T cell activity with a CD8 antibody, the pro-tumorigenic effect of LISS was significantly reduced, suggesting that LISS exerts its tumor-promoting function by regulating CD8+ T cell activity.
To clarify the molecular mechanism by which LISS affects T cell-mediated anti-tumor immunity, the team performed high-throughput sequencing analysis and found that genes regulated by LISS were mainly enriched in the IFN-γ signaling and antigen presentation pathways. Further studies revealed that LISS, through its unique double stem-loop structure, binds to the kinase domain of CamKIIγ and specifically inhibits its phosphorylation-mediated activation of STAT1 at serine 727 (S727). Although LISS does not regulate the classical active site STAT1 Y701, this regulatory effect significantly reduces the transcription of MHC-I-related target genes. Nanomaterial-encapsulated antisense oligonucleotides targeting LISS degradation in CRC cells effectively restore the activation of the IFN-γ-STAT1-MHC-I signaling axis in tumor tissues, enhance ICB efficacy in CRC, prolong mouse survival, and improve survival rates.
In summary, this study reveals that overexpression of LISS in CRC cells suppresses the IFN-γ-STAT1-MHC-I signaling axis, leading to immune evasion in both MSI and MSS-type CRC. Inhibition of LISS sensitizes ICB efficacy, suggesting that LISS is a potential immunotherapeutic target for CRC.
Professor Hu Ying from the School of Life Science and Technology, Harbin Institute of Technology, is the corresponding author. Dr. Lin Qingyu, Associate Researcher from Zhengzhou Institute of Advanced Technology, Harbin Institute of Technology, is the first author, and Associate Researcher Wang Xingwen from the School of Life Science is the co-first author. The study was supported by Dr. Hou Guixue from BGI-Shenzhen and Professor Li Li from Harbin Medical University Cancer Hospital. This project was funded by the National Natural Science Foundation of China and the National Postdoctoral Science Foundation.
Article link：https://doi.org/10.1038/s41392-026-02671-y