Microenvironment-responsive multi-free radical generations towards immunogenic tumor cell ferroptosis

Ferroptosis, an iron-dependent non-apoptotic cell death mode, has emerged as a promising strategy for tumor therapy, yet the direct delivery of iron-based nanomedicines will inevitably trigger marked anaphylactic reactions in normal tissues. Non-ferrous nanomedicines have thus attracted ever-increasing attentions, while their rational designs, functional exploitations and therapeutic mechanism clarifications remain great challenges. Herein, we report a palladium-tungsten oxide/carbon (Pd-WO 2.90 /C, PWC) nanomedicine via a green, facile and high-efficiency fabrication strategy. In response to the tumor microenvironment (TME, such as mild acidity, overexpressed peroxide (H 2 O 2 ) and glutathione (GSH)), PWC exhibits intrinsic catalase (CAT)-like activity and triggers the generation of multiple reactive oxygen species (ROS) including hydroxyl radical ( • OH), singlet oxygen ( 1 O 2 ) and carbon free radical ( • C). More importantly, PWC achieves ferroptosis-like tumor regression with enhanced specificity and meanwhile efficiently induces immunogenic cell death (ICD) in tumor cells without inducing iron-related adverse reactions in normal tissues. Mechanistically, PWC depletes intracellular GSH to inactivate glutathione peroxidase 4 (GPX4), promotes lipid peroxidation (LPO) accumulation, and simultaneously triggers multi-Radical burst to amplify oxidative stress, collectively driving ferroptosis-like cell death. Furthermore, the PWC-induced ICD elicits robust anti-tumor immune responses, which further suppresses tumor growth and metastasis. In vitro and in vivo experiments consistently validate the superior anti-tumor efficacy and excellent biocompatibility of PWC, and the in-depth exploration of its therapeutic mechanism. This work not only develops a non-ferrous nanomedicine for efficient ferroptosis-like therapy and ICD induction, but also offers a versatile design paradigm for the development of next-generation non-ferrous nanomedicines.