In recent years, genes associated with immunogenic cell death (ICD)-related genes have garnered significant interest as potential targets for immunotherapy. As a frontier in cancer treatment, immunotherapy has notably enhanced the therapeutic outcomes for cancer patients. However, since only a subset of patients benefits from this treatment approach, there is an imperative need for biomarker research to enhance patient sensitivity to immunotherapy. Expression of ICD-related genes and clinical patient data were sourced from The Cancer Genome Atlas (TCGA) database. Utilizing univariate Cox regression analysis, we constructed a signature for predicting the overall survival of colon adenocarcinoma (COAD) patients. A genomic feature analysis was performed, incorporating tumor mutation burden (TMB) and copy number variation (CNV). The immunological characteristics were analyzed via the ssGSEA and GSEA algorithms, with the resulting data visualized using R software (version 4.2.1). According to the univariate regression analysis for COAD, AIM2 emerged as the gene most significantly associated with overall survival among the 32 ICD-related genes in the TCGA dataset. Patients were divided into two groups based on high or low AIM2 expression, and genomic differences between the groups were explored. Patients expressing high levels of AIM2 had a higher TMB and a lower CNV. In addition, these patients had elevated immune checkpoint, immune cell, and immune function scores, thus indicating increased sensitivity to immunotherapy. TIDE analysis further confirmed that these patients were likely to respond more effectively to immunotherapy. Subclass mapping analysis corroborated our findings, demonstrating that patients with high AIM2 expression responded more positively to immunotherapy. Additionally, our study found that the suppression of AIM2 could significantly enhance the proliferation, invasion, and migration capabilities of colon cancer cells. In this research, we identified a novel prognostic signature suggesting that patients with higher AIM2 expression levels are more likely to respond favorably to immunotherapy.