Diselenide-Based Dual-Responsive Prodrug as Pyroptosis Inducer Potentiates Cancer Immunotherapy
Shu-Cheng Wan1, Meng-Jie Ye2, Qi-Chao Yang1
1The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, 430079, China.
Abstract:
Pyroptosis is demonstrated to trigger antitumor immunity and represents a promising new strategy to potentiate cancer immunotherapy. The number of potent pyroptosis inducers, however, is limited and without tumor-targeting capability, which inevitably causes damage in normal tissues. Herein, a small molecular prodrug of paclitaxel-oxaliplatin is rationally synthesized, which can be covalently self-assembled with diselenide-containing cross-linking (Dse11), producing a diselenide nanoprodrug (DSe@POC) to induce pyroptosis for the first time. The diselenide bonds within DSe@POC can be split by high glutathione in the tumor microenvironment (TME) and reactive oxygen species induced by photodynamic therapy, thus possessing excellent TME on-target effects. Additionally, DSe@POC is able to elicit intense pyroptosis to remodel the immunostimulated TME and trigger a robust immune response. Furthermore, combined αPD-1 therapy effectively inhibits the growth of remote tumors through the abscopal effect, amplifies a long-term immune memory response to reject rechallenged tumors, and prolongs survival. Collectively, DSe@POC, as the first TME dual-responsive diselenide-based pyroptosis inducer, will open up an attractive approach for cancer immunotherapy.
Insights
A novel diselenide nanoprodrug (DSe@POC) induces pyroptosis, enhancing antitumor immunity. This targeted approach remodels the tumor microenvironment (TME) and potentiates cancer immunotherapy, offering a promising new strategy.
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.
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