BackgroundMast cells, comprising a crucial component of the tumor immune milieu, modulate neoplastic progression by secreting an array of pro- and antitumorigenic factors. Numerous extant studies have produced conflicting conclusions regarding the impact of mast cells on the prognosis of patients afflicted with lung adenocarcinoma (LUAD).MethodsEmploying single-cell RNA sequencing (scRNA-seq) analysis, mast cell-specific marker genes in LUAD were ascertained. Subsequently, a mast cell-related genes (MRGs) signature was devised to stratify LUAD patients into high- and low-risk cohorts based on the median risk value. Further investigations were conducted to assess the influence of distinct risk categories on the tumor microenvironment. The prognostic import and capacity to prognosticate immunotherapy benefits of the MRGs signature were corroborated using four external cohorts. Ultimately, the functional roles of SYAP1 were validated throughin vitroexperimentation.ResultsAfter scRNA-seq and bulk RNA-seq data analysis, we established a prognostic signature consisting of nine MRGs. This profile effectively distinguished favorable survival outcomes in both the training and validation cohorts. In addition, we identified the low-risk group as a population more effective for immunotherapy. In cellular experiments, we found that silencing SYAP1 significantly reduced the proliferation, invasion and migratory capacity of LUAD cells while increasing apoptosis.ConclusionOur MRGs signature offers valuable insights into the involvement of mast cells in determining the prognosis of LUAD and may prove instrumental as a navigational aid for immunotherapy selection, as well as a predictor of immunotherapy response in LUAD patients.