Ferroptosis is a new form of regulated cell death that shows promise for tumor treatment. Nevertheless, most of the current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies, and it would be of substantial clinical significance to develop new ferroptosis-inducing strategies that have improved tumor specificity and modulability. In this study, we have constructed a polydopamine-based nanoplatform (Fe(II)PDA@LAP-PEG-cRGD) for the efficient loading of Fe 2+ ions and β-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. Specifically, the PDA nanostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe 2+ ions. Meanwhile, the NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis, which could facilitate the bioreduction of the concurrently released β-lapachone and enhance intracellular H 2 O 2 formation to promote the Fe 2+ -mediated lipid peroxidation. This robust strategy for the remote activation and enhancement of ferroptosis in vivo holds promise for the management of a wide variety of tumor indications in a clinical context.