Targeting VPS4 elicits STING-driven anti-tumor immunity to suppress rhabdomyosarcoma growth

Area of Science:

• Cell Biology
• Immunology
• Cancer Biology

Background:

• VPS4, an AAA+ ATPase, is crucial for ESCRT-mediated membrane remodeling.
• Cancer cells often exhibit VPS4A or VPS4B dependency, presenting a therapeutic vulnerability.
• VPS4 inhibition can cause cancer cell death and influence the immune microenvironment.

Purpose of the Study:

• To elucidate the mechanisms by which VPS4 inhibition affects the tumor immune microenvironment.
• To investigate the role of the cGAS-STING pathway in VPS4 inhibition-induced immune signaling.
• To evaluate the therapeutic potential of VPS4 inhibition in a murine rhabdomyosarcoma model.

Main Methods:

• Murine rhabdomyosarcoma (RMS) cells were treated with VPS4 inhibitors.
• Analysis of cytokine and immune signaling pathways, including NF-κB and cGAS-STING.
• Orthotopic syngeneic RMS tumor models were used to assess anti-tumor effects and immune infiltration.
• Genetic deletion of STING was employed to determine its role.

Main Results:

• VPS4 inhibition upregulated cytokine and innate immune signaling via the cGAS-STING-TBK1-IRF3 axis, driven by cytoplasmic mitochondrial DNA.
• VPS4 inhibition suppressed tumor growth and increased tumor immunogenicity in vivo.
• STING was not essential for VPS4 inhibition-induced cell death but was critical for optimal anti-tumor immunity, including immune cell infiltration.

Conclusions:

• VPS4 inhibition exhibits a dual mechanism of action: direct tumor cell killing and promotion of anti-tumor immunity.
• The cGAS-STING pathway is a key mediator of VPS4 inhibition-induced immune responses.
• Targeting VPS4 vulnerability represents a promising cancer therapeutic strategy with potential to enhance immune-mediated tumor rejection.