Simple SummaryIntrinsic immunogenic cell death (ICD) property plays an important role in the prognosis and immune microenvironment of patients with lung adenocarcinoma (LUAD). In this study, we performed an overall multi-omics analysis of the intrinsic ICD property and developed a risk scoring system. We found two distinct ICD-associated transcriptomic molecular patterns (termed ICD-high and ICD-low). We identified and validated ICDrisk subtypes (ICDrisk) which can effectively predict overall survival (OS) in LUAD patients and immunotherapeutic response across Pan-cancer. Our results may help to elucidate the underlying molecular mechanisms of intrinsic immunogenicity and heterogeneous responses to immunotherapy in LUAD patients.AbstractRecent studies have highlighted the combination of activation of host immunogenic cell death (ICD) and tumor-directed cytotoxic strategies. However, overall multiomic analysis of the intrinsic ICD property in lung adenocarcinoma (LUAD) has not been performed. Therefore, the aim of this study was to develop an ICD-based risk scoring system to predict overall survival (OS) and immunotherapeutic efficacy in patients. In our study, both weighted gene co-expression network analysis (WGCNA) and LASSO-Cox analysis were utilized to identify ICDrisk subtypes (ICDrisk). Moreover, we identify genomic alterations and differences in biological processes, analyze the immune microenvironment, and predict the response to immunotherapy in patients with pan-cancer. Importantly, immunogenicity subgroup typing was performed based on the immune score (IS) and microenvironmental tumor neoantigens (meTNAs). Our results demonstrate that ICDrisk subtypes were identified based on 16 genes. Furthermore, high ICDrisk was proved to be a poor prognostic factor in LUAD patients and indicated poor efficacy of immune checkpoint inhibitor (ICI) treatment in patients with pan-cancer. The two ICDrisk subtypes displayed distinct clinicopathologic features, tumor-infiltrating immune cell patterns, and biological processes. The ISlowmeTNAhighsubtype showed low intratumoral heterogeneity (ITH) and immune-activated phenotypes and correlated with better survival than the other subtypes within the high ICDrisk group. This study suggests effective biomarkers for the prediction of OS in LUAD patients and immunotherapeutic response across Pan-cancer and contributes to enhancing our understanding of intrinsic immunogenic tumor cell death.