Identifying potential targets for lung cancer intervention by analyzing the crosstalk of cancer‐associated fibroblasts and immune and metabolism microenvironment

Cancer-associated fibroblasts (CAFs) have been reported to play a crucial role in the tumor microenvironment and progression.The data used in this study were obtained from the Cancer Genome Atlas and Gene Expression Omnibus databases, and all analyses were performed using R software.We first quantified the CAFs infiltration through single sample gene set enrichment analysis in the TCGA and combined GEO cohort (GSE30219, GSE37745, and GSE50081). Our result showed that patients with high levels of CAF infiltration were associated with worse clinical features and poor prognosis. Immune microenvironment analysis indicated that high CAF infiltration might result in increased infiltration of immune cells, including aDC, B cells, CD8+ T cells, cytotoxic cells, DC, eosinophils, iDC, macrophages, mast cells, neutrophils, NK CD56dim cells, NK cells, pDC, and T cells. Correlation analysis showed a significant positive correlation between CAFs and M2 macrophages, while a negative correlation was found between CAFs and glycerophospholipid metabolism. Kaplan-Meier survival curves indicated that glycerophospholipid metabolism was a protective factor against lung cancer. Biological enrichment analysis showed that pathways such as allograft rejection, epithelial-mesenchymal transition, KRAS signaling, TNF-α signaling, myogenesis, IL6/JAK/STAT3 signaling, IL2/STAT5 signaling were upregulated in the patients with high CAF infiltration. Moreover, patients with high CAF infiltration had a lower proportion of immunotherapy responders. Genome analysis showed that low CAFs infiltration was associated with high genome instability. We identified FGF5 and CELF3 as key genes involved in the interaction between CAFs, M2 macrophages, and glycerophospholipid metabolism, and further analyzed FGF5. In vitro experiments showed that FGF5 promoted the proliferation, invasion and migration of lung cancer cells and was primarily localized in the nucleoli fibrillar center.Our study provides novel insights into the roles of CAFs in lung cancer progression and the underlying crosstalk of tumor metabolism and immune microenvironment.