Omics · study · 2026
RNF43 p.G659fs Leads to Natural Killer Cell Dysfunction in MSI-high Colorectal Cancer Through PI3K/AKT/mTOR Signaling and HLA-E Upregulation
Listed in NCBI GEO
The RNF43 p.G659fs (RNF43659mut) mutation occurs in 8% of colorectal cancers (CRCs) and is enriched in microsatellite instability-high (MSI-H) tumors.
Description
While RNF43659mut promotes tumor growth through PI3K/AKT/mTOR activation independent of WNT signaling, its immunologic effects are poorly defined. We show that RNF43659mut shapes an immunosuppressive NK cell landscape in MSI-H CRC.
Single-cell RNA sequencing and multiplex immunohistochemistry revealed increased NK cell infiltration in RNF43659mut tumors, yet these cells displayed inhibitory phenotypes. Bulk RNA-seq and flow cytometry of NK cells co-cultured with RNF43659mut isogenic lines and MSI-H patient-derived organoids demonstrated reduced functional NK subsets, decreased activation markers, increased inhibitory receptors, and impaired cytotoxicity.
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Mechanistically, RNF43659mut-mediated PI3K/AKT activation induced HLA-E expression, suppressing NK cell function. Pharmacological or siRNA-mediated PI3K/AKT inhibition restored NK cell activity and enhanced tumor cell killing. Spatial analysis of MSI-H patient tumors revealed close proximity between NKG2A⁺NK cells and HLA-E⁺ tumor cells, which were themselves adjacent to PI3K/AKT-activated tumor cells, highlighting a localized immunosuppressive niche.
These findings uncover an immune evasion mechanism in MSI-H CRC, implicating the PI3K/AKT-HLA-E/NKG2A axis as a promising therapeutic target to overcome immunotherapy resistance.
Links
Get the data
- GEO FTP directory ftp.ncbi.nlm.nih.gov/geo/series/GSE342nnn/GSE342684 ↗
download · from NCBI GEO
Where it is published
- GEO accession page ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE342684 ↗
landing page · from NCBI GEO
Documentation and papers
- PRJNA1508766 ncbi.nlm.nih.gov/bioproject/PRJNA1508766 ↗
project · from NCBI GEO
Topics
- Stated by source
- Expression profiling by high throughput sequencing · Homo sapiens
- From keywords
- Life Sciences
- Inferred from text
- Cancer 75% · RNA sequencing 75% · Sequencing 75% · Single-cell RNA sequencing 75%
Provenance · 1 source records, 11 field assertions
| Source | Key | Last seen | Raw |
|---|---|---|---|
| NCBI GEO | GSE342684 | 15 d ago | JSON v1 |
| Field | Assertion | Extractor | Evidence |
|---|---|---|---|
| access_level | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[disease].local:disease:cancer | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[field].local:field:life-sciences | mapping · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| concepts[method].geo_series_type:expression-profiling-by-high-throughput-sequencing | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /gdstype |
| concepts[modality].local:modality:rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:sequencing | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[modality].local:modality:single-cell-rna-seq | enrichment · NCBI GEO | keyword-concept-rules@1.0.0 | title+description (75%) |
| concepts[organism].NCBITaxon:9606 | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /taxon |
| description | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /summary |
| publication_date | source · NCBI GEO | connector:ncbi_geo@1.0.0 | |
| title | source · NCBI GEO | connector:ncbi_geo@1.0.0 | /title |