Transforming Intratumor
Bacteria into Immunopotentiators
to Reverse Cold Tumors for Enhanced Immuno-chemodynamic Therapy of
Triple-Negative Breast Cancer
Immunotherapy
of triple-negative breast cancer (TNBC)
has an unsatisfactory
therapeutic outcome due to an immunologically “cold”
microenvironment. Fusobacterium nucleatum (F. nucleatum) was found to be colonized in triple-negative
breast tumors and was responsible for the immunosuppressive tumor
microenvironment and tumor metastasis. Herein, we constructed a bacteria-derived
outer membrane vesicle (OMV)-coated nanoplatform that precisely targeted
tumor tissues for dual killing of F. nucleatum and cancer cells, thus transforming intratumor bacteria into immunopotentiators
in immunotherapy of TNBC. The as-prepared nanoparticles efficiently
induced immunogenic cell death through a Fenton-like reaction, resulting
in enhanced immunogenicity. Meanwhile, intratumoral F. nucleatum was killed by metronidazole, resulting
in the release of pathogen-associated molecular patterns (PAMPs).
PAMPs cooperated with OMVs further facilitated the maturation of dendritic
cells and subsequent T-cell infiltration. As a result, the “kill
two birds with one stone” strategy warmed up the cold tumor
environment, maximized the antitumor immune response, and achieved
efficient therapy of TNBC as well as metastasis prevention. Overall,
this strategy based on a microecology distinction in tumor and normal
tissue as well as microbiome-induced reversal of cold tumors provides
new insight into the precise and efficient immune therapy of TNBC.