RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.

RNF43 p.G659fs mutation promotes immune evasion in MSI-high colorectal cancer by activating PI3K/AKT/mTOR signaling and upregulating HLA-E, impairing natural killer cell function.

• Why it matters: Understanding how tumor mutations influence immune responses is crucial for developing effective immunotherapies, especially since MSI-high colorectal cancers often resist current treatments.
• What they did: The study used single-cell RNA sequencing, multiplex immunohistochemistry, bulk RNA sequencing, and functional assays on tumor samples and cell models to analyze NK cell behavior and signaling pathways in RNF43 659mut tumors.
• The result: Findings show that RNF43 659mut activates PI3K/AKT/mTOR signaling, leading to increased HLA-E expression and NK cell inhibition, suggesting targeting this pathway could improve immunotherapy outcomes.