ArticleBiology direct2026
Integrative single-cell and bulk analyses reveal ATF4-associated immune suppression and WNT/β-catenin signaling in osteosarcoma.
Article in Biology direct, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundOsteosarcoma (OS) is highly heterogeneous and often exhibits an immunosuppressive tumor microenvironment, contributing to poor outcomes. The cell-type-resolved role of the ATF/CREB stress-response network, particularly ATF4, remains unclear in OS.
methodsWe integrated public OS single-cell RNA-seq and bulk transcriptome cohorts. Single-cell analyses included malignant program discovery (cNMF), regulon inference (SCENIC), and cell-cell communication (CellChat). Bulk cohorts (TARGET and GEO) were used to build and validate a prognostic model. ATF4-associated immune features were assessed using ESTIMATE, immune deconvolution, and TIDE-related metrics. WNT/β-catenin activity was evaluated by gene-set scoring. ATF4-related drugs were screened using DSigDB/Enrichr and assessed by docking. Sorafenib was selected for molecular dynamics simulation. ATF4 function was validated by siRNA knockdown (MG63, U2OS) and overexpression (HOS).
resultsA stress-associated malignant program showed enriched ATF/CREB activity and prominent signaling interactions. Intersecting its markers with ATF/CREB genes identified ATF3/ATF4/CREB5, which were used to construct an ATF/CREB-associated risk score (ACS) that stratified survival in TARGET and external cohorts. ATF4 showed the most consistent adverse prognostic association and remained an independent factor in multivariate analyses. ATF4-high tumors were associated with a more immunosuppressive profile and stronger WNT/β-catenin signaling, and these features tracked with the ACS. Among the compounds tested in silico, sorafenib ranked highest in docking, and subsequent molecular dynamics simulations suggested that the ATF4-sorafenib interaction can remain stable. In cell-based assays, silencing ATF4 curtailed proliferation, colony formation, and migration, accompanied by reduced β-catenin, CyclinD1, and c-MYC. By contrast, ATF4 overexpression led to the opposite pattern.
conclusionOur results place ATF4 at the intersection of stress-related tumor programs, immune suppression, and WNT/β-catenin activation in OS, and this pattern is associated with poorer clinical outcomes. The ACS offers a practical way to stratify risk, and sorafenib warrants further evaluation as a potential ATF4-oriented therapeutic lead.
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