Abstract
Lung cancer is prevalent worldwide and is a major cause of cancer-related mortality. Despite being the primary model for immunotherapy research, the response rates of lung cancer patients to immunotherapy are unsatisfactory. Furthermore, research on immunogenic cell death (ICD) in lung cancer is limited, which limits the development of strategies that combine ICD-related therapies with immunotherapy. In this study, we compiled and summarized 69 genes associated with ICD and developed an IRS. Across seven independent datasets, the IRS was identified as an independent prognostic factor. IRS was positively associated with multiple tumor proliferation pathways and negatively associated with immune-related pathways. Additionally, IRS negatively correlated with the infiltration of various immune cells, supporting its association with survival outcomes. Based on the correlation between IRS and immune activity, we validated the ability of IRS to predict immunotherapy efficacy across seven immunotherapy datasets and demonstrated that patients who respond to immunotherapy tend to have a lower IRS. Moreover, utilizing single-cell RNA sequencing, we revealed the role of mast cells in the TME with the highest IRS. Through interactions with various receptors on macrophages, endothelial cells, and tumor cells, mast cells promote tumor progression, providing a comprehensive explanation for poor prognosis and lack of response to immunotherapy in patients with high IRS. Our study offers new guidance for combination therapies in lung adenocarcinoma patients and elucidated the mechanism by which mast cells contribute to cancer development within the TME.