# KRAS Withdrawal in Cholangiocarcinoma Leads to Immune Infiltration and Tumor Regression

## TL;DR

Turning off the KRAS gene in liver cancer leads to tumor shrinkage and immune response, suggesting a new treatment approach.

## Contribution

The study demonstrates that KRAS inhibition can trigger tumor regression and immune infiltration in cholangiocarcinoma.

## Key findings

- KRAS withdrawal in a mouse model leads to over 90% tumor regression within 7 days.
- KRAS inhibition is associated with immune infiltration of activated CD8+ T cells.
- IL-15 and CCL17 cytokine secretion is linked to delayed tumor progression in CCA models.

## Abstract

Cholangiocarcinoma (CCA) is a liver cancer subtype with poor survival rates. KRAS mutations are found in 15–40% of CCA, representing a new potential treatment target. Whether KRAS inhibition leads to CCA tumor regression is unknown, partly due to the lack of conditional animal models. A conditional TRE.Kras
G12D/Trp53 knock‐out (TKP) CCA mouse model is engineered using the transposon system and CRISPR‐Cas9. Withdrawal of Kras
G12D results in >90% tumor regression by day 7, accompanied by infiltration and enrichment of activated CD8+ T cells, shown by IHC, co‐IF staining, and single‐cell RNA‐Seq. Bulk RNA‐Seq of TKP cell line suggested that Kras
G12D withdrawal stimulates the transforming growth factor beta pathway and induces senescence. Cytokine array characterizes the secretion of pro‐inflammatory factors, including IL‐15 and CCL17. Lentiviral overexpression of murine IL‐15 and CCL17 delays CCA tumor progression in a syngeneic transplant model. Consistently, expression of IL‐15 resulted in blockade of tumor progression in the TKP CCA model. These findings highlight the importance of oncogenic Kras in CCA tumor maintenance and underscore KRAS inhibition as a potential therapeutic approach for CCA.

Cholangiocarcinoma (CCA) driven by oncogenic KRAS depends on its continuous activation for tumor maintenance. Using a conditional KRAS model, the authors show that turning off KRAS triggers rapid tumor regression accompanied by immune cell infiltration and cytokine release. The findings uncover a KRAS–senescence–immune signaling axis and highlight KRAS inhibition as a promising therapeutic strategy for CCA.