Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity

Sci Adv. 2022 Feb 18;8(7):eabj7002. doi: 10.1126/sciadv.abj7002. Epub 2022 Feb 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exosomes* / genetics
  • Exosomes* / metabolism
  • Humans
  • Macrophages / metabolism
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Neoplasms* / therapy
  • STAT6 Transcription Factor / genetics
  • STAT6 Transcription Factor / metabolism
  • Tumor Microenvironment / genetics
  • Tumor-Associated Macrophages


  • STAT6 Transcription Factor
  • STAT6 protein, human