Zinc‐Complex Orchestrating Pyroptosis for Hypoxia‐Tolerant Photoimmunotherapy

ABSTRACT 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 Zn 2+ ‐complexes through constructing enhanced D‐A systems. Zn 2+ coordination efficiently enhances the ISC by lowering the excited singlet‐triplet energy gap (ΔE S1−T1 ), leading to exceptionally high ROS generation efficiency through Type I mechanisms to overcome hypoxia and the immunosuppression of tumor microenvironment. In these Zn 2+ ‐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 Zn 2+ ‐complexes, propelling advancements in cancer treatment strategies.