The complex regulatory landscape of GSDMC and GSDMD mutations in colorectal cancer: A double-edged sword for survival outcomes

Colorectal cancer (COAD) is a major cause of cancer-related mortality, with advancements in treatment offering limited improvements in survival, particularly for advanced cases where the 5-year survival rate remains around 12.5 %. The inherent heterogeneity of COAD necessitates the identification of novel biomarkers to improve prognosis and therapeutic strategies. This study investigates the roles of gasdermin family members GSDMC and GSDMD as potential prognostic biomarkers and therapeutic targets in COAD. We found that GSDMC is consistently upregulated across multiple datasets, particularly in microsatellite instability-high (MSI) tumors, and is associated with poor survival outcomes, suggesting an oncogenic role. In contrast, GSDMD expression is reduced in microsatellite stable (MSS) advanced tumors, implying a role in immune evasion and tumor progression. Notably, mutations in GSDMC and GSDMD were linked to the upregulation of genes such as ARNTL, PRAGD, EFNA5, and GRAMD1B, as well as the downregulation of CDC24, indicating disruptions in pathways related to angiogenesis, vesicle trafficking, cell adhesion, and cell cycle progression. Moreover, high GSDMC expression correlates with increased immune cell infiltration, including macrophages and CD8+ T cells, within the tumor microenvironment, which is crucial for anti-tumor immunity. These findings underscore the potential of targeting GSDMC and, to a lesser extent, GSDMD to modulate the tumor microenvironment and enhance the efficacy of immunotherapies in COAD. This study contributes to the growing understanding of the interaction between gasdermin mutations and the immune microenvironment, offering insights into the development of GSDMD inhibitors as a therapeutic strategy.