Zinc‐Complex Orchestrating Pyroptosis for Hypoxia‐Tolerant Photoimmunotherapy

Photon-driven pyroptosis represents an advanced and promising modality in anti-tumor immunotherapy, offering new avenue in combating cancer recurrence and metastasis. Essential metal-complex shows great potential in photoimmunotherapy, which however hardly generates reactive oxygen species (ROS) to active photoimmunotherapy under light irradiation due to low spin-orbit coupling (SOC) resulting in intersystem crossing (ISC) being blocked. To address this challenge, we innovatively proposed the concept of essential-metal ion as an electron-withdrawing group to modulate the donor-acceptor (D-A) system, thereby significantly improving ROS generation efficiency. As a proof of concept, we designed and synthesized a series of Zn2+-complexes through constructing enhanced D-A systems. Zn2+ coordination efficiently enhances the ISC by lowering the excited singlet-triplet energy gap (ΔES1-T1), leading to exceptionally high ROS generation efficiency through Type I mechanisms to overcome hypoxia and the immunosuppression of tumor microenvironment. In these Zn2+-complexes, Zn-TPY-TPA-DTZ can photodynamically damage lysosomes to trigger pyroptosis, which further induce anti-tumor immune responses through the promotion of immunogenic cell death (ICD), and ultimately generates a robust anti-tumor immune response and curbed the proliferation of 4T1 tumors in vivo. This study provides systematic guidance for the rational design of advanced Zn2+-complexes, propelling advancements in cancer treatment strategies.