Second Affiliated Hospital of Guangzhou Medical University

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.

Necrotizing enterocolitis (NEC) is a severe gastrointestinal disease affecting premature infants, yet its precise pathogenic mechanisms remain unclear. While immunothrombosis, an interplay between inflammation and coagulation, is well recognized in systemic inflammatory diseases, its role in NEC pathogenesis and local intestinal regulation has been incompletely characterized. Here, we combine multi-omics profiling, histopathological analyses, and functional studies using clinical NEC samples and neonatal mouse models. We demonstrate prominent intestinal thromboinflammation in NEC, histologically characterized by immunothrombosis with infiltrating CD177⁺ neutrophils, activated platelets, and fibrin deposition. We show that extensive formation of CD177⁺ neutrophil-platelet aggregates (NPAs) amplifies intestinal injury through neutrophil extracellular trap (NET)-mediated thromboinflammation. Blocking CD177⁺ NPAs or inhibiting NET formation significantly alleviates NEC severity in mouse models. Clinically, elevated CD177⁺ NPA levels correlate with NEC severity and increased thrombotic biomarkers, highlighting their potential as diagnostic and prognostic biomarkers. Importantly, prophylactic administration of low-molecular-weight heparin (LMWH) disrupts NPA formation, reduces NET burden, and improves survival in experimental NEC. Collectively, these findings establish CD177⁺ NPAs as central drivers of NEC pathogenesis, support a thromboinflammatory framework for NEC, and highlight LMWH therapy and CD177⁺ NPA monitoring as possible clinically translatable strategies for neonatal care.