On-site unlocking and local detonation: A programmed death ligand 1-targeted nanoplatform achieving precise immune...

Immunotherapy represents a pioneering approach in clinical cancer treatment, but its application is often limited by insufficient immune stimulation and off-target side effects. Therefore, developing novel nanomaterials capable of precisely reshaping the tumor microenvironment (TME) is crucial for enhancing the efficacy of tumor immunotherapy. Herein, we constructed a "precision immune bomb" DOX@MZIF-P3 embodying a "PD-L1-targeted, on-site unlocking, local detonation" strategy. It actively targets and blocks highly expressed programmed death ligand 1 (PD-L1) on tumor cells, achieving tumor accumulation while attenuating immune evasion. In response to the TME, it depletes glutathione (GSH) and releases effector substances including doxorubicin (DOX), Mn²⁺, and Zn²⁺. Specifically, DOX induces apoptosis via DNA damage and elevates intratumoral H₂O₂ levels. Mn²⁺ generates reactive oxygen species (ROS) through Fenton-like reactions to trigger ferroptosis, while simultaneously sensitizing and augmenting the stimulator of interferon genes (STING) pathway. Zn²⁺ overload induces tumor cell pyroptosis and further promotes immunogenic cell death (ICD). Additionally, synergy between activated STING pathway and ICD enhances immune cell infiltration in tumor tissue and increases the levels of related inflammatory factors in the TME, ultimately promoting immunotherapy. This strategy precisely activates tumor immunity while significantly reducing off-target toxicity, effectively inhibiting primary tumor growth and blocking metastasis, providing a new paradigm for precision tumor immunotherapy.