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Updated: Jul 8, 2026
A Preclinical Mouse Model of Osteosarcoma to Define the Extracellular Vesicle-mediated Communication Between Tumor and Mesenchymal Stem Cells
Published on: May 6, 2018
Entosis remodels the immune microenvironment of osteosarcoma by regulating macrophage polarization: An integrated
Guoling Huang1, Yongbo Xiao2, Hongliang Zhang3
1Department of Pathology, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.
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.
Insights
Entosis, a programmed cell death, shows tumor-suppressive effects in osteosarcoma by activating the immune microenvironment and remodeling macrophage function. This offers new avenues for precision prognosis and immunotherapy.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- Entosis, a non-apoptotic programmed cell death, plays an unclear role in osteosarcoma's immune microenvironment.
- Understanding entosis mechanisms is crucial for osteosarcoma treatment.
Purpose of the Study:
- To investigate the clinical significance and immune remodeling mechanisms of entosis in osteosarcoma.
- To identify potential prognostic markers and therapeutic targets related to entosis.
Main Methods:
- Integrated multi-omics data (TARGET-OS, GEO) with in vitro experiments.
- Employed ssGSEA, WGCNA, scRNA-seq, and cell-cell communication analysis.
- Developed and validated a six-gene prognostic risk model.
Main Results:
- High entosis activity correlated with favorable prognosis and an activated immune microenvironment.
- Macrophages, particularly the Macro_CXCL2 subset, were key targets of entosis regulation.
- Entosis remodeling involved SPP1-CD44 and TNF signaling axes, impacting macrophage polarization and immune crosstalk.
- A six-gene prognostic model (CD163, FCGR2A, NPC2, CD209, SAMHD1, IKZF1) showed strong predictive power.
Conclusions:
- Entosis exhibits tumor-suppressive and immune-activating roles in osteosarcoma via macrophage remodeling.
- Entosis presents novel targets for precision prognosis and immunotherapy in osteosarcoma.
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