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Sci Adv ; 8(7): eabj7002, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35179953

RESUMO

Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is a novel approach to induce antitumor immunity. The M2 phenotype is controlled by key transcription factors such as signal transducer and activator of transcription 6 (STAT6), which have been "undruggable" selectively in TAMs. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which selectively silences STAT6 expression in TAMs. In syngeneic models of colorectal cancer and hepatocellular carcinoma, exoASO-STAT6 monotherapy results in >90% tumor growth inhibition and 50 to 80% complete remissions. Administration of exoASO-STAT6 leads to induction of nitric oxide synthase 2 (NOS2), an M1 macrophage marker, resulting in remodeling of the tumor microenvironment and generation of a CD8 T cell-mediated adaptive immune response. Collectively, exoASO-STAT6 represents the first platform targeting transcription factors in TAMs in a highly selective manner.


Assuntos
Exossomos , Neoplasias , Exossomos/genética , Exossomos/metabolismo , Humanos , Macrófagos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Microambiente Tumoral/genética , Macrófagos Associados a Tumor
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