# RUNX1 restrains STAT1-GITRL signaling to shape an immunosuppressive CRC microenvironment

## TL;DR

RUNX1 helps create an immunosuppressive environment in colorectal cancer by reducing GITRL signaling and increasing Treg cell infiltration.

## Contribution

This study reveals a novel RUNX1/STAT1/GITRL signaling axis that modulates the tumor immune microenvironment in CRC.

## Key findings

- RUNX1 expression is negatively correlated with GITRL levels and linked to increased Treg infiltration in CRC tissues.
- RUNX1 inhibits GITRL-GITR signaling, suppressing CD8+ T cell activation and promoting Treg infiltration.
- RUNX1 interacts with STAT1 to block its dimerization and transcriptional activation of GITRL.

## Abstract

The oncogenic role of RUNX1 in epithelial tumors is increasingly recognized, however, its function and mechanism within the tumor immune microenvironment (TME) of colorectal cancer (CRC) remain unclear. This study investigates the contribution of RUNX1 to TME remodeling in CRC. Analysis of clinical CRC tissues revealed that RUNX1 expression is negatively correlated with GITRL levels in tumor cells and is associated with increased infiltration of Treg cells. Functional studies demonstrated that RUNX1 impairs GITRL-GITR signaling, thereby promoting Treg cell infiltration while suppressing CD8+ T cell activation. Consequently, elevated RUNX1 expression enhanced the sensitivity of CRC tumors to GITR agonistic antibody therapy in a C57BL/6J mouse model. Mechanistically, RUNX1 interacts with STAT1 to inhibit its dimerization and subsequent transcriptional activation of GITRL, thereby suppressing GITRL expression. Our findings highlight the RUNX1/STAT1/GITRL axis as a potential therapeutic target for GITR-based immunotherapy in CRC.