2. Academic Validation
  3. OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours

OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours

  • Nature. 2026 Apr;652(8110):740-751. doi: 10.1038/s41586-026-10149-8.
Luojia Yang # 1 2 3 4 5,  Paul A Renauer # 1 2 3,  Kaiyuan Tang 1 2 3 4 5,  Josh Saskin 1 2 3 4 5 6,  Liqun Zhou 1 2 3 4 7,  Charles Zou 1 2 3 4 5,  Seok-Hoon Lee 1 2 3,  Madison Fox 1 2 3 4 7,  Samuel Johnson-Noya 1 2,  Benedict Weiss 1 2,  Stephanie Deng 1 2 3 6,  Paris Fang 1 2,  Binfan Chen 1 2 3,  Giacomo Sferruzza 1 2 3,  Saba Fooladi 1 2 3,  Kai Zhao 1 2 3,  Daniel Park 1 2,  Feifei Zhang 1 2 3,  Jiayi Tu 8,  Jing Chen 8,  Jennifer Moliterno 9,  Murat Gunel 9,  Lei Peng 10 11 12 13,  Sidi Chen 14 15 16 17 18 19 20 21 22 23 24
Affiliations

Affiliations

  • 1 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
  • 2 System Biology Institute, Yale University, West Haven, CT, USA.
  • 3 Center for Cancer Systems Biology, Yale University, West Haven, CT, USA.
  • 4 Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA.
  • 5 Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA.
  • 6 Yale MD-PhD Program, Yale University School of Medicine, New Haven, CT, USA.
  • 7 Immunobiology Program, Yale University, New Haven, CT, USA.
  • 8 Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • 9 Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
  • 10 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 11 System Biology Institute, Yale University, West Haven, CT, USA. [email protected].
  • 12 Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. [email protected].
  • 13 Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 14 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 15 System Biology Institute, Yale University, West Haven, CT, USA. [email protected].
  • 16 Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. [email protected].
  • 17 Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. [email protected].
  • 18 Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA. [email protected].
  • 19 Yale MD-PhD Program, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 20 Immunobiology Program, Yale University, New Haven, CT, USA. [email protected].
  • 21 Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 22 Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 23 Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • 24 Department of Biomedical Informatics and Data Science, Yale University School of Medicine, New Haven, CT, USA. [email protected].
  • # Contributed equally.
PMID: 41741641 DOI: 10.1038/s41586-026-10149-8
Abstract

Chimeric antigen receptor (CAR)-natural killer (NK) cell therapies hold promise for solid tumours but remain limited because of poor tumour infiltration, persistence and resistance in the tumour microenvironment1-4. Here, to identify gain-of-function targets that enhance CAR-NK cell efficacy, we performed an unbiased in vivo CRISPR activation screen followed by a barcoded targeted in vivo open reading frame screen in primary human CAR-NK cells. We identified and comprehensively validated OR7A10, a G protein-coupled receptor (GPCR), as the top candidate. Engineering CAR-NK cells with OR7A10 cDNA (a CRISPR-independent method with a simple manufacturing strategy) enhanced their proliferation, activation, degranulation, cytokine production, death ligand expression, Chemokine Receptor expression, cytotoxicity, persistence, metabolic fitness and tumour microenvironment resistance. Moreover, exhaustion in primary human NK cells derived from multiple peripheral blood and cord blood donors was reduced. OR7A10 gain-of-function CAR-NK cells displayed strong in vivo efficacy across multiple solid tumour models. For example, 100% complete response with long-term tumour control and survival benefit in an orthotopic breast Cancer mouse model were achieved. These findings establish OR7A10-engineered CAR-NK cells as a highly potent and scalable off-the-shelf therapeutic for solid tumours.

Figures
Products