Integrative analysis of single-cell and bulk RNA sequencing reveals inflammatory mechanisms of cancer-induced nerve injury and enables prognostic modeling in lung adenocarcinoma.

BACKGROUND: Cancer-induced nerve injury (CINI) is implicated in unfavorable clinical outcomes across multiple cancer types. However, its biological role and prognostic value remain insufficiently characterized in lung adenocarcinoma (LUAD). METHODS: Bulk RNA sequencing, single-cell RNA sequencing, and spatial transcriptomics datasets were integrated to investigate CINI-related molecular features in LUAD. Survival analysis was performed to evaluate the prognostic significance of CINI-related transcriptional activity. Immune infiltration analysis, functional enrichment analysis, and tumor microenvironment (TME) profiling were conducted to explore the association between CINI and immune environment. Weighted gene co-expression network analysis (WGCNA) and machine learning algorithms were further applied to construct a CINI-related prognostic signature. Single-cell and spatial transcriptomic analyses were used to identify CINI-associated epithelial cells, characterize their developmental states, and explore potential intercellular communication patterns. In vitro experiments were performed to validate the functional relevance of the selected risk gene. RESULTS: Survival analysis indicated a significant negative association between CINI activity and overall survival in LUAD patients across multiple transcriptomic cohorts. Single-cell and spatial transcriptomic analyses identified malignant transcriptional features, increased developmental plasticity, and preferential enrichment in metastatic lesions of CINI-associated epithelial cells. We further established a CINI-related prognostic model, and in vitro experiments supported the functional relevance of PLEK2 in LUAD cell proliferation and migration. CONCLUSION: This study provided an integrative multi-omics characterization of CINI in LUAD and suggested that CINI activity was associated with TME remodeling and prognosis. These findings highlight the potential value of CINI-related signatures for prognostic stratification and future therapeutic exploration.