# Bimetallic Cu/Fe-MOF-based heterojunction sonozymes for triple amplification of sono-immunotherapy through activating tumor-specific cuproptosis and cGAS-STING pathway

## TL;DR

A new nanoplatform enhances antitumor immunity by combining sonodynamic therapy, cuproptosis, and immune pathway activation.

## Contribution

First TME-responsive nanoplatform integrating sonocatalytic activity, cGAS-STING activation, and cuproptosis for triple immune amplification.

## Key findings

- Fe-Cu-MOF@MnO2-x heterojunctions enable enhanced ROS production and multienzyme-mimic activities.
- Combination therapy using FCMM achieved complete elimination of primary tumors and control of distant tumors.
- Activation of cGAS-STING pathway and cuproptosis significantly boosts dendritic cell maturation and immune response.

## Abstract

Initiating ROS-induced ICD and activating innate immune pathways are promising strategies for reprogramming immunosuppressive TME and eliciting persistent antitumor immune responses.

To realize the cascade amplification of antitumor immune response, we report for the first time a TME-responsive nanoplatform through coating oxygen-vacancy-doped MnO2-x onto Cu-doped Fe-based MOF (FCM) for the fabrication of Fe-Cu-MOF@MnO2-x (FCMM) heterojunctions. The introduction of Cu ions in Fe-MOF and the encapsulation of MnO2-x enable FCMM as a high-efficiency sonozyme, achieving enhanced ROS production through heterojunction-mediated sonodynamic activity amplification and Fe/Cu/Mn-ion-triggered multienzyme-mimic activities including Fenton/Fenton-like reaction, GSH depletion, and hypoxia alleviation.

The reversal of the immunosuppressive tumor microenvironment occurs through the ROS-triggered ICD and the enhancement of DC cell maturation. More importantly, the activation of the Mn ions-mediated cGAS-STING pathway further boosts the maturation of DCs. In addition, the released Cu ions can induce cuproptosis, achieving triple amplification of antitumor immune response.

The combination therapy of CDT, SDT, cuproptosis, and cGAS-STING activation via FCMM, achieved complete elimination of primary tumor and significant controlled the growth of distant tumor. This work combines sonocatalytic nanomedicine with immune modulation strategy through integrating ROS amplification, cGAS-STING activation, and cuproptosis effect into a single nanoplatform, providing new insights for the clinical application of sono-immunotherapy.