Gold nanozyme-decorated Cu/Mn MOFs simultaneously enhances immunogenicity and alleviates immunosuppression in triple-negative breast cancer.

[INTRODUCTION] The efficacy of immunotherapy in triple-negative breast cancer (TNBC) is primarily challenged by its inherent low immunogenicity, which is further undermined by the immunosuppressive activity of tumor-associated polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). The hypoxic microenvironment renders PMN-MDSCs susceptible to ferroptosis and exacerbates immunosuppression.

[OBJECTIVES] This study aimed to design a multifunctional nanoplatform comprising Cu/Mn bimetallic metal-organic frameworks decorated with gold (Au) nanozymes (CMAP MOFs) that simultaneously enhances tumor immunogenicity and alleviates immunosuppression.

[METHODS] The characteristics of the nanosystem were evaluated using transmission electron microscopy, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and ultraviolet-visible spectrophotometry. In vitro experiments employed Western blotting, immunofluorescence, and flow cytometry to investigate the mechanisms of enhanced immunogenicity and alleviated immunosuppression in 4T1 cells. In vivo experiments evaluated the therapeutic efficacy of the nanosystem in BALB/c mice bearing implanted 4T1 tumors.

[RESULTS] Within tumor cells, the CMAP MOFs undergo GSH-responsive disintegration. The released Cu/Mn ions catalyze Fenton-like reaction to induce tumor cell ferroptosis and mitochondrial DNA damage, activating cGAS-STING pathway, and facilitating CD8 T cells recruitment. Simultaneously, released Au nanozymes catalyze HO conversion to O, alleviating hypoxia and preventing PMN-MDSCs ferroptosis and associated immunosuppression. While the immunogenicity-enhancing CMP MOFs group increased CD8⁺ T cell infiltration from 21% to 28.3% with 74.1% tumor growth inhibition, the combined immunogenicity enhancement and immunosuppression relief CMAP MOFs group further boosted CD8⁺ T cell infiltration to 32.4% with superior tumor growth inhibition of 81.3%, with IFN-γ and GZMB expression elevated by 2.2-fold and 2.0-fold (CMP MOFs) and 3.4-fold and 3.0-fold (CMAP MOFs) compared to control. This strategy offers a promising approach for enhancing immunotherapy in TNBC patients.