Efferocytosis-associated transcriptomic patterns characterize prognosis and immune landscape in osteosarcoma

Area of Science:

• Oncology
• Immunology
• Genomics

Background:

• Osteosarcoma (OS) is a heterogeneous bone cancer with poor prognosis.
• The role of efferocytosis (clearance of apoptotic cells) in OS progression and immune evasion is not well understood.

Purpose of the Study:

• To investigate the role of efferocytosis in osteosarcoma.
• To develop a prognostic signature based on efferocytosis pathways.
• To elucidate the underlying mechanisms of efferocytosis in OS.

Main Methods:

• Integrated multi-cohort data (TARGET-OS, GEO) for analysis.
• Quantified efferocytosis pathways using ssGSEA and identified gene modules with WGCNA.
• Developed and validated a prognostic signature using machine learning.
• Performed functional enrichment, immune infiltration, and single-cell/spatial transcriptomic analyses.
• Investigated MAGEA11 function in vitro and in vivo.

Main Results:

• A robust prognostic signature was developed, stratifying OS patients into distinct risk groups.
• High-risk patients showed increased M2 macrophages, altered immune checkpoints, and predicted immunotherapy sensitivity.
• Efferocytosis activity was enriched in OS cells, with MAGEA11 identified as a key mediator.
• MAGEA11 promoted OS growth and immunosuppression via a Gas6-MERTK/AXL-dependent efferocytosis pathway, polarizing macrophages to an M2 phenotype.

Conclusions:

• Established an efferocytosis-related prognostic signature for osteosarcoma.
• Elucidated MAGEA11's mechanism in promoting OS immunosuppression through an efferocytosis circuit.
• Highlighted efferocytosis as a critical driver of the OS microenvironment and a potential therapeutic target.