Enhanced pyroptosis induction with pore-forming gene delivery for osteosarcoma microenvironment reshaping

Area of Science:

• Oncology
• Immunology
• Biotechnology

Background:

• Osteosarcoma lacks effective treatments, with immunotherapy hindered by a suppressive tumor microenvironment (TME).
• The role of gasdermins (GSDMs), particularly gasdermin E (GSDME), in osteosarcoma and TME modulation is not well understood.

Purpose of the Study:

• To investigate the correlation between GSDME expression and osteosarcoma prognosis and immune infiltration.
• To develop a gene delivery system for upregulating GSDME expression to reshape the osteosarcoma TME via pyroptosis.

Main Methods:

• Analysis of GSDME expression in osteosarcoma patients.
• Development of a novel vector (LPAD) for GSDME gene delivery.
• Molecular dynamics simulations to assess vector hydration properties.
• Evaluation of pyroptosis induction and subsequent immune responses.

Main Results:

• Low GSDME expression was observed and correlated with poor prognosis and reduced immune infiltration.
• The LPAD vector effectively delivered the GSDME gene, upregulating protein expression and inducing pyroptosis.
• Pyroptosis led to the release of proinflammatory cytokines, increased immune cell infiltration, and activated adaptive immunity, creating an immunogenic TME.

Conclusions:

• GSDME plays a significant role in osteosarcoma immune infiltration and patient prognosis.
• GSDME gene delivery via the LPAD vector is a promising strategy to inhibit osteosarcoma by inducing pyroptosis and reprogramming the TME for enhanced immunotherapy.