Conditionally Activatable Pyroptosis-Inducing Agents for Cancer Therapy.

Area of Science:

• Immunology
• Oncology
• Biochemistry

Background:

• Pyroptosis is a promising immunogenic cell death pathway for cancer immunotherapy.
• Current pyroptosis-inducing agents (PyAs) lack specificity, causing off-target toxicity in normal and immune cells.
• Conditional activation of PyAs in response to disease biomarkers is crucial for biosafety.

Purpose of the Study:

• To develop a general strategy for creating activatable PyAs.
• To design PyAs that specifically induce pyroptosis in cancer cells.
• To improve the safety and efficacy of pyroptosis-based cancer immunotherapy.

Main Methods:

• Development of a new class of photoactive PyAs termed PyPSs.
• Incorporation of specific targeting and sensing properties into PyPSs.
• Synthesis of a hypoxia-activatable PyPS-NF as a proof-of-concept.

Main Results:

• PyPSs exhibit endoplasmic reticulum targeting, hypoxia tolerance, and sensing capabilities.
• PyPS-NF specifically induced pyroptosis in hypoxic tumor cells.
• Demonstrated favorable immunotherapeutic efficacy against solid tumors.

Conclusions:

• Established a general design strategy for tailoring activatable PyAs.
• Achieved precise control over GSDME-mediated pyroptosis.
• Highlighted the potential of conditionally activatable PyAs for advancing cancer immunotherapy.