Diselenide-Based Dual-Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Pyroptosis is a potent inducer of antitumor immunity and a promising strategy for cancer immunotherapy.
• Current pyroptosis inducers lack tumor-targeting capabilities, leading to damage in normal tissues.

Purpose of the Study:

• To develop a novel tumor-targeting pyroptosis inducer for enhanced cancer immunotherapy.
• To investigate the efficacy of a diselenide nanoprodrug (DSe@POC) in triggering pyroptosis and remodeling the tumor microenvironment (TME).

Main Methods:

• Synthesis of a small molecular prodrug of paclitaxel-oxaliplatin.
• Covalent self-assembly with diselenide-containing cross-linking (Dse11) to form DSe@POC.
• Evaluation of DSe@POC's TME on-target effects, pyroptosis induction, and combined therapy efficacy with αPD-1.

Main Results:

• DSe@POC demonstrated TME dual-responsive properties, splitting in the tumor microenvironment via glutathione and reactive oxygen species.
• DSe@POC effectively induced pyroptosis, remodeled the immunostimulated TME, and triggered a robust immune response.
• Combined DSe@POC and αPD-1 therapy inhibited remote tumor growth (abscopal effect), amplified immune memory, and prolonged survival.

Conclusions:

• DSe@POC is the first TME dual-responsive diselenide-based pyroptosis inducer.
• This novel nanoprodrug offers an attractive approach for potentiating cancer immunotherapy.
• The findings highlight the potential of targeted pyroptosis induction for effective cancer treatment.