68 A subset of cancers, known as Microsatellite Instability (MSI) and deficient DNA Mismatch Repair (dMMR) cancers, are more visible to the immune system than others. Because their DNA repair systems are defective, these tumours are more likely to be recognised and attacked by immune cells and tend to respond better to immunotherapy. Scientists have not fully understood why, until now. Researchers from the Keck School of Medicine of USC have discovered a biological feedback loop that helps the immune system recognise and attack colorectal cancers with MSI or dMMR. In mice, they found that two genes, Death Receptor 5 (DR5) and Ligase 3 (Lig3), help drive a cycle of tumour cell death and immune system activation. The study, funded in part by the National Institutes of Health and published in the journal Gastroenterology, may suggest a way to make immunotherapy more effective against cancers that respond poorly to treatment. To investigate what makes MSI and dMMR cancers different, lead author Lin Zhang, PhD, professor of medicine and Oncology at the Keck School, and his colleagues created a mouse model of the disease by disabling a key DNA repair gene in tumour cells. They implanted the altered cells into healthy mice to watch the immune response unfold, tracking changes in cell signalling, cell behaviour, and gene activity as the animals mounted an immune response to the tumours. Two genes, DR5 and Lig3, emerged as key players. The DNA repair defect caused the tumour cells to increase activity of the DR5 gene, triggering their own destruction. As the cells died, they released extrachromosomal circular DNA (eccDNA), small circular pieces of DNA separate from the cell’s main genetic material. More eccDNA was released when the Lig3 gene was highly active, and this eccDNA activated a broader immune response, creating a positive feedback loop that helped the immune system mount an ongoing attack against the tumour. The researchers then analysed gene expression data from human colorectal cancer patients and found that tumours with higher levels of DR5 and Lig3 activity responded better to treatment with immune checkpoint inhibitors, a type of cancer immunotherapy. “One of the most encouraging parts of the study was seeing that the same signals showed up in patient tumours,” Zhang said. “That suggests we’re uncovering a mechanism that could be clinically relevant.” MSI and dMMR tumours make up about 15% of colorectal cancers and are known for their high mutational burden, which generates neoantigens and makes them prime candidates for immunotherapies. However, not all patients respond equally, and resistance remains a challenge. Immune checkpoint inhibitors have already transformed treatment for many patients with these molecular subtypes, achieving durable responses where traditional chemotherapy often falls short, but the new feedback loop offers a clearer picture of why some tumours are more immunogenic than others. Experts note that while MSI and dMMR status is routinely tested in colorectal cancer to guide immunotherapy decisions, additional molecular markers like DR5 and Lig3 expression could further refine patient selection, particularly for those whose tumours show partial or no response to current checkpoint inhibitors. Zhang will continue working with Heinz-Josef Lenz, MD, a co-author of the study, who contributed clinical expertise and access to patient datasets that allowed the team to compare laboratory findings with real-world outcomes. Looking ahead, the researchers aim to explore whether drugs that activate the DR5 pathway or increase eccDNA release could make immunotherapy more effective, and whether DR5 and Lig3 could help personalise treatment by predicting who is most likely to benefit. More research is needed before these approaches can be tested in patients, including studies of human colorectal tumour cells. The findings may also have implications for other MSI and dMMR cancers, including some ovarian and endometrial cancers, which Zhang and his team hope to explore next. “We’ve gathered enough evidence to suggest that this feedback loop is an important piece of the puzzle,” Zhang said. “Our hope is that these findings can someday help make cancers more visible to the immune system and more responsive to immunotherapy treatment.”