Zinc-Complex Orchestrating Pyroptosis for Hypoxia-Tolerant Photoimmunotherapy

Area of Science:

• Oncology
• Immunotherapy
• Materials Science

Background:

• Photon-driven pyroptosis is a promising anti-tumor immunotherapy strategy.
• Metal complexes for photoimmunotherapy often struggle with reactive oxygen species (ROS) generation due to inefficient intersystem crossing (ISC).

Purpose of the Study:

• To develop metal complexes with enhanced ROS generation for photoimmunotherapy.
• To investigate the use of essential metal ions as electron-withdrawing groups to improve ROS production.
• To design and synthesize novel Zn²⁺-complexes for enhanced anti-tumor immune responses.

Main Methods:

• Designed and synthesized Zn²⁺-complexes with modulated donor-acceptor (D-A) systems.
• Investigated the effect of Zn²⁺ coordination on intersystem crossing (ISC) and ROS generation efficiency.
• Evaluated the anti-tumor efficacy of a specific complex (Zn-TPY-TPA-DTZ) in vitro and in vivo, assessing pyroptosis induction and immune response.

Main Results:

• Zn²⁺ coordination significantly enhanced ISC by reducing the singlet-triplet energy gap (ΔE_S1-T1).
• The developed Zn²⁺-complexes exhibited high ROS generation efficiency via Type I mechanisms.
• Zn-TPY-TPA-DTZ successfully induced lysosomal damage, triggering pyroptosis and immunogenic cell death (ICD).
• In vivo studies demonstrated that Zn-TPY-TPA-DTZ curbed 4T1 tumor proliferation and generated robust anti-tumor immune responses.

Conclusions:

• Essential metal ions can be effectively utilized as electron-withdrawing groups to enhance ROS generation in photoimmunotherapy.
• The designed Zn²⁺-complexes show significant potential for overcoming tumor microenvironment challenges like hypoxia and immunosuppression.
• This work provides a framework for designing advanced Zn²⁺-complexes for improved cancer treatment strategies.