Pyroptosis-Mediated Molecular Subtypes and Tumor Microenvironment Infiltration Characterization in Colon Cancer

The role of pyroptosis, which is also a kind of cell-intrinsic death mechanism, in tumorigenesis and cancer progression has been revolutionized. However, the expression of pyroptosis-related genes (PYGs) in colon cancer (CC) and their prognostic value remain unclear. In this study, we comprehensively identified two PYG-mediated molecular subtypes with a distinct tumor microenvironment (TME) in 1,415 CC samples, which were based on 10 PYGs. The six-gene signature (pyroptosis score, PY-score) was constructed to quantify the molecular patterns of individual tumors using a least absolute shrinkage and selection operator (LASSO)-Cox regression model through the differentially expressed genes between the two molecular subtypes. Significant infiltration of activated immune cells (such as M1 macrophages and cytotoxic T cells) was observed in the low PY-score group, while naive and suppressive immune cells (such as naive CD8⁺ T cells and M2 macrophages) dominated in the high PY-score group. CC patients in the low PY-score group showed not only significant survival advantage but also sensitivity to immune checkpoint inhibitor treatment, anti-epidermal growth factor receptor (EGFR) therapy, and chemotherapy. Overall, this work revealed that the PYGs played a vital role in the formation of heterogeneity in the TME. The analysis of the PYG-mediated molecular patterns helps in understanding the characterization of TME infiltration and provides insights into more effective therapeutic strategies.