The important role of pyroptosis in tumor progression has been well characterized in recent years. However, little is known about the impact of tumor pyroptosis characteristics on patient prognosis and tumor microenvironment (TME) as well as efficacy of immunotherapy. In this study, we successfully classified colon cancer samples into three pyroptosis characterizations with different prognosis and TME cell infiltration patterns based on the expression of pyroptosis-related genes. Cluster 2, with the characterizations of immunosuppression, was classified as immune-desert cell infiltration patterns. Cluster 3, with the patterns of immune-inflamed cell infiltration, had the feature of an activated innate and adaptive immunity and significant prolonged survival. The activation of stromal pathways including EMT, angiogenesis and TGF-β in cluster 1 may mediate the impaired immune penetration of this cluster, which was classified as immune-excluded cell infiltration patterns. Our results demonstrated the PyroSig signature was a robust and independent biomarker for predicting patient prognosis. Patients with low PyroSig signature was confirmed to be correlated with treatment advantages and significant prolonged survival in two anti-checkpoint immunotherapy cohorts. This study identified three pyroptosis-related subtypes with distinct molecular features, clinical and microenvironment cell infiltration patterns in colon cancer, which could promote individualized immunotherapy for colon cancer.