Nanocatalytic Phase Separation Augments Tumor-specific cGAS-STING Activation for Spinal Metastasized Breast Cancer Metalloimmunotherapy.

Abstract

The cGAS-STING pathway is a pivotal therapeutic target for antitumor immunity, yet clinical translation of its small-molecule agonists is hindered by poor tumor specificity, suboptimal pharmacokinetics, and systemic off-target effects. Here, we report a nanocatalytic strategy based on a tumor microenvironment (TME)-responsive iron-oxygen-vanadium metal-organic framework (MIL-88B(Fe─O─V)) that enables tumor-specific cGAS-STING activation via catalytic phase separation for targeted immunotherapy in spinal metastasized breast cancer. Specifically, MIL-88B(Fe─O─V) undergoes disassembly within the acidic TME to release iron ions and polyoxovanadate (POV). Iron ions enable catalytic reactive oxygen species (ROS) generation to release double-stranded DNA (dsDNA) and induce immunogenic cell death (ICD). Critically, we demonstrate for the first time that POV potently promotes liquid-liquid phase separation (LLPS) of cGAS, enhancing its affinity for dsDNA and amplifying STING pathway activation in dendritic cells (DCs) without systemic immune dysregulation. Such combinational ICD induction and LLPS-driven cGAS activation synergistically boost DC maturation, cytotoxic T-cell responses, and establish durable antitumor immunity. In spinal metastasis models, MIL-88B(Fe─O─V) not only achieves robust tumor regression and prolonged survival, but also mitigates cancer-related pain via IFN-β-mediated suppression of TRPV1 channel activity. Our findings unveil a paradigm of nanocatalytic STING activation for advanced metastatic cancer metalloimmunotherapy and cancer pain alleviation.