Entosis remodels the immune microenvironment of osteosarcoma by regulating macrophage polarization: An integrated study based on multi-omics data and in vitro experiments

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BACKGROUND: Entosis is a non-apoptotic form of programmed cell death. Its clinical significance and mechanism of immune microenvironment remodeling in osteosarcoma remain poorly understood. METHODS: Multi-omics data from TARGET-OS and GEO were integrated with in vitro experiments. ssGSEA, WGCNA, scRNA-seq, pseudotime analysis, and cell-cell communication were used to assess Entosis activity and immune association. A prognostic risk model was constructed and validated. In vitro experiments (qPCR, flow cytometry, Western blot, ELISA) validated Entosis regulation of macrophage polarization. RESULTS: High Entosis activity was significantly correlated with favorable prognosis and a highly activated immune microenvironment in osteosarcoma patients. scRNA-seq identified macrophages as the core target cells of Entosis regulation, and the Macro_CXCL2 subset was characterized as the functional subpopulation with the highest Entosis score at the terminal differentiation stage. Cell communication analysis revealed that, under high Entosis conditions, macrophages enhanced crosstalk with other immune cells via the SPP1-CD44 and TNF signaling axes. A six-gene prognostic model (CD163, FCGR2A, NPC2, CD209, SAMHD1, IKZF1) demonstrated robust performance across multiple datasets. In vitro experiments further confirmed that high-Entosis tumor cells upregulated CXCL12 secretion in a paracrine manner, driving macrophages toward a specific functional phenotype. Mechanistically, Entosis activation was dependent on the ROCK signaling pathway and synergized with the hypoxia, TNFα-NFκB, and MAPK pathways to coordinately regulate malignant cell stemness and immune microenvironment remodeling. CONCLUSION: Entosis exerts tumor-suppressive and immune-activating effects in osteosarcoma by remodeling macrophage function, offering new targets for precision prognosis and Entosis-directed immunotherapy.

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