Work

A DR5/Ligase 3-Mediated Feedback Loop Perpetuates Immunogenicity in Mismatch Repair Deficient Colorectal Cancer

Year: 2026

Type: article

Abstract: BACKGROUND & AIMS: Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) and microsatellite instability (MSI) are believed to be intrinsically immunogenic and respond more favorably to immune checkpoint inhibitor (ICI) therapy. However, a significant fraction of dMMR/MSI CRCs do not respond or eventually develop resistance to ICIs. The mechanisms underlying dMMR/MSI-associated immunogenicity is unclear. The aim of this study was to investigate the role and mechanism of MSI-induced antitumor immunity in CRCs. METHODS: We used transplant syngeneic tumor models, immune cell coculture assays, and air-liquid interface culture of tumor-derived organoids to investigate the mechanism by which dMMR elicits an antitumor immune response. We also analyzed the gene expression databases of CRC cancer patients receiving ICI treatment. RESULTS: We found that inactivating Mlh1 causes endoplasmic reticulum stress and death receptor 5 (Dr5)-mediated apoptosis in syngeneic colorectal tumors. Sustained immune response against Mlh1-deficient tumors requires nuclear Ligase 3 (Lig3)-mediated release of extrachromosomal circular DNAs from apoptotic cells. A feedback Dr5/Lig3 amplification loop perpetuates apoptosis and immune cell activation in Mlh1-deficient syngeneic tumors. This feedback mechanism is critical for the response to ICI therapy in mice, which is supported by a significant association between DR5 or LIG3 expression and the efficacy of ICI therapy in cancer patients. CONCLUSIONS: Our results reveal a functional link between dMMR and antitumor immunity, which may be useful for improving ICI therapy in tumors with different MMR statuses.

Source: Gastroenterology

DOI: 10.1053/j.gastro.2026.06.014