SPP1 in Immunosuppressive Signaling in Lung Adenocarcinoma: Bulk and Single-Cell Transcriptomic Analysis.

BACKGROUND

Secreted phosphoprotein 1 (SPP1) has been implicated in various tumors and is known to correlate with immune infiltration and poor prognosis. However, its functional role as an immune communication mediator within the lung adenocarcinoma (LUAD) tumor microenvironment (TME) remains poorly defined. This study aimed to investigate the prognostic value of SPP1 and its association with inferred intercellular communication patterns in LUAD.

METHODS

We integrated bulk RNA-seq datasets (GSE7670, GSE43458, TCGA-LUAD) and single-cell RNA-seq data (GSE123902) to identify differentially expressed genes and candidate signaling-related molecules. Protein-protein interaction networks and CytoHubba analysis were used to screen hub genes. Single-cell clustering and cell type annotation were performed using Seurat and SingleR. CellChat analysis was applied to construct ligand-receptor signaling networks, with a focus on the SPP1 axis. Immune infiltration and immunotherapy-related features were evaluated via CIBERSORT, ssGSEA, and immune checkpoint expression analysis. Survival analysis was conducted using TCGA and GEPIA datasets.

RESULTS

SPP1 was significantly overexpressed in LUAD tumor tissues and primarily secreted by macrophages and monocytes. CellChat analysis suggested that SPP1 may participate in intercellular communication with other immune cells through CD44 and multiple integrin receptors, representing a prominent inferred signaling pattern in the LUAD microenvironment. High SPP1 expression was associated with elevated infiltration of regulatory T cells, myeloid-derived suppressor cells (MDSCs), and increased expression of immunosuppressive checkpoint molecules including CD276 and PDCD1LG2. Moreover, elevated SPP1 expression correlated with epithelial-mesenchymal transition, PI3K-AKT pathway activation, increased tumor mutational burden (TMB), and significantly poorer survival outcomes.

CONCLUSION

Our study suggests that SPP1 may serve as a prognostic biomarker and a candidate immune communication-related molecule in LUAD. These findings provide transcriptomic evidence supporting a potential association between SPP1 and immunosuppressive remodeling in the LUAD microenvironment, although further validation in larger single-cell cohorts is warranted to confirm these intercellular communication patterns. These findings may provide a rationale for future studies evaluating macrophage-lymphocyte signaling networks in LUAD immunotherapy.