Ferroptosis can activate immune response via inducing tumor cells immunogenic cell death (ICD), and antitumor immunity in turn booststhe efficacy of ferroptosis by excreting interferon gamma (IFN-𝜸), which shows a promising combo for synergistically amplified tumor treatment. However, their combination is strictly limited by the complexity of tumor microenvironment, including poor ferroptosis response and immunosuppressive factors in tumor. Herein, a metal-phenolic networks (MPNs) nanoplatform with all-active components is constructed to favor the ferroptosis-immunotherapy cyclical synergism. The photothermal MPNs are assembled via coordination between tannic acid (TA) and metal-ion complex of Fe 3+ /Mn 2+ , through which a PD-L1 inhibiting DNAzyme (DZ) is loaded to regulate the immunosuppressive PD-1/PD-L1 pathway. After intracellular delivery, each component of MPNs exerts their respective functions: Fe 2+ is in situ generated from Fe 3+ by TA reduction to trigger ferroptosis, while DZ is activated by Mn 2+ to effectively silence PD-L1. With external laser irradiation, photothermal therapy is initiated to synergize with ferroptosis for enhanced ICD, which induces strong antitumor immunes. Combined with DZ-mediated PD-L1 suppression, a cyclically amplified tumor ferroptosis-immunotherapy is achieved, resulting in obliteration of both primary and distant tumor. This work provides a smart, simple, yet robust nanomedicine-based combination for self-amplified tumor treatment.

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