Dual functional nanoplatforms potentiate osteosarcoma immunotherapy via microenvironment modulation.

Area of Science:

• Biomedical Engineering
• Oncology
• Immunology

Background:

• Osteosarcoma (OS) is an aggressive bone tumor with limited treatment options.
• Cellular autophagy is impaired in OS, hindering effective therapeutic strategies.
• Mitochondrial autophagy inhibition is a key feature observed at the transcriptomic level in OS.

Purpose of the Study:

• To investigate the therapeutic potential of a dual-functional metal nanoplatform (MnSx) for osteosarcoma (OS).
• To explore MnSx's ability to shift autophagy from a protective role to a tumor-killing effect in OS.
• To evaluate MnSx's efficacy in combination with immune checkpoint inhibitors for complete OS remission.

Main Methods:

• Bioinformatic analysis of clinical OS samples to identify impaired autophagy.
• Transcriptomic analysis to validate mitochondrial autophagy inhibition in OS.
• In vitro and in vivo studies using MnSx nanoplatform for therapeutic intervention.

Main Results:

• MnSx facilitates intracellular H2S generation, promoting mitochondrial autophagy via USP8 S-sulfhydration.
• MnSx activates the cGAS-STING pathway, enhancing autophagy and tumor cell death.
• In vivo, MnSx activates autophagy, matures dendritic cells, and activates cytotoxic T lymphocytes, leading to tumor eradication.

Conclusions:

• MnSx shows potential as a dual-functional therapeutic platform for osteosarcoma.
• Targeting autophagy via MnSx offers a novel strategy for OS treatment.
• Combination therapy with immune checkpoint inhibitors holds promise for complete OS remission.