Engineering bispecific exosome activators of T cells to target immune checkpoint inhibitor-resistant metastatic melanoma

  • Nat Biotechnol. 2026 Jan 5. doi: 10.1038/s41587-025-02890-8.
Shuo Liu  #  1  2 ,  Mengrui Liu  #  1  2 ,  Zhenzhen Wang  #  3  4 ,  Shiqi Hu  1  2 ,  Kaiyue Zhang  1  2 ,  Chao Lu  1 ,  Xiao Cheng  1  2 ,  Ming Shen  1  2 ,  Jianing Bi  4 ,  Dashuai Zhu  5  6 ,  Ke Cheng  7  8  9
Affiliations
  • 1. Department of Biomedical Engineering, Columbia University, New York, NY, USA.
  • 2. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
  • 3. Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill/Raleigh, NC, USA.
  • 4. Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, USA.
  • 5. Department of Biomedical Engineering, Columbia University, New York, NY, USA. [email protected].
  • 6. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. [email protected].
  • 7. Department of Biomedical Engineering, Columbia University, New York, NY, USA. [email protected].
  • 8. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA. [email protected].
  • 9. Seymour, Paul, and Gloria Milstein Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 41491256 DOI: 10.1038/s41587-025-02890-8
Abstract

Cancer Immunotherapy with immune checkpoint inhibitors (ICIs) is often limited by an immunosuppressive tumor microenvironment (TME). Simultaneous targeting of the TME and immune checkpoints is a promising approach to address this limitation. Here we develop an inhalable exosome system that enables co-display of two inhibitory ligands and apply it to treat lung metastases of ICI-resistant melanoma. As immune exclusion in this context is often mediated by Wnt/β-catenin signaling, we harnessed the Alix sorting domain for tandem display of PD-1 and FZD8 to block PD-L1 and Wnt7b, which is overexpressed in ICI-resistant melanoma. This technology, called bispecific exosome activator of T cells (BEAT), enables uniform 1:1 co-display of two proteins on the exosome surface. We show that BEAT concurrently recruits and activates CD8⁺ T cells to reprogram the TME, yielding robust antitumor activity in ICI-resistant melanoma mouse models. Inhaled BEAT outperforms linked dual antibody targeting PD-L1 and Wnt7b in vivo. This approach to tandem protein display may be applicable to diverse ICI-resistant cancers.

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