XIAP induces inflammation and promotes colorectal cancer progression

Colorectal cancer (CRC) is one of the most diagnosed malignancies worldwide, with chronic inflammation playing a critical role in its pathogenesis and progression. Surgery represents the primary treatment option, though some patients suffer from relapse, leading to considerable morbidity and mortality. A better molecular understanding of CRC pathogenesis is therefore essential for identifying patients at increased risk of recurrence and improving clinical management. Here we identified the X-linked inhibitor of apoptosis protein (XIAP) as an independent predictor of overall survival in primary resected CRC patients. To model CRC patients with low versus high XIAP expression, we established conditional mouse lines for intestinal epithelial cell (IECs)-specific Xiap knock-out and XIAP knock-in, and employed a colitis-associated murine model for CRC. We found that XIAP promotes inflammatory signalling and exacerbates colitis-driven colorectal tumorigenesis by shaping a distinct tumor inflammatory microenvironment characterized by increased immune-cell infiltration, including neutrophils, and enhanced vascularisation. The pro-inflammatory role of XIAP was further validated in CRC patient-derived organoids and human CRC tumor specimens. Collectively, our findings identify XIAP as a potential biomarker of CRC-associated inflammation and a candidate marker for identifying patients at increased risk of disease recurrence. Moreover, these results provide a rationale for exploring XIAP-targeting strategies as a potential component of multimodal therapeutic approaches for CRC.