Cascade-catalytic microneedles convert the tumor cholesterol shield into an oxidative spear for self-amplifying ferroptosis-driven cancer immunotherapy.

Abstract

Ferroptosis holds great promise for cancer immunotherapy, yet elevated cholesterol levels in tumor cells impose substantial structural and functional barriers to ferroptosis. Here, a cascade-catalytic nanocomposite microneedle platform (CSMZC MNs) is developed to convert this tumor-intrinsic cholesterol shield into an oxidative spear for ferroptosis-amplified cancer immunotherapy. By integrating superoxide dismutase (SOD) and cholesterol oxidase (COD) within Mn-doped zeolitic imidazolate framework nanoparticles and embedding them into dissolvable poly(γ-glutamic acid) microneedles, the platform enables localized intratumoral delivery and coordinated catalytic activation. After tumor cell internalization, the SOD-COD-Mn²⁺ cascade rewires redox metabolism and membrane lipid homeostasis by depleting cholesterol and 7-dehydrocholesterol, thereby dismantling tumor resistance to ferroptosis while amplifying reactive oxygen species generation and lipid peroxidation. This self-reinforcing oxidative amplification induces ferroptosis-associated immunogenic cell death and promotes cytosolic accumulation of nuclear and mitochondrial DNA, resulting in endogenous cGAS-STING activation. Meanwhile, Mn²⁺ enhances cGAS sensitivity to cytosolic DNA and amplifies type I interferon-mediated innate immune signaling. Through catalytic amplification and immune remodeling, CSMZC MNs reshape the immunosuppressive tumor microenvironment and elicit systemic T cell-mediated antitumor immunity against both primary and distant tumors. This work establishes an agonist-free immunometabolic strategy for converting tumor-protective cholesterol metabolism into a therapeutic vulnerability for tumor immunotherapy.