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.