OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours
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- Article
- Published: 25 February 2026
OR7A10 GPCR engineering boosts CAR-NK therapy against solid tumours
- Luojia Yang1,2,3,4,5 na1,
- Paul A. Renauer1,2,3 na1,
- Kaiyuan Tang
orcid.org/0009-0006-4538-65191,2,3,4,5,
- Josh Saskin
orcid.org/0000-0001-5372-96961,2,3,4,5,6,
- Liqun Zhou
orcid.org/0000-0002-3561-74951,2,3,4,7,
- Charles Zou1,2,3,4,5,
- Seok-Hoon Lee1,2,3,
- Madison Fox1,2,3,4,7,
- Samuel Johnson-Noya1,2,
- Benedict Weiss
orcid.org/0009-0008-6165-23911,2,
- Stephanie Deng1,2,3,6,
- Paris Fang1,2,
- Binfan Chen1,2,3,
- Giacomo Sferruzza1,2,3,
- Saba Fooladi1,2,3,
- Kai Zhao1,2,3,
- Daniel Park
orcid.org/0009-0002-6862-66351,2,
- Feifei Zhang1,2,3,
- Jiayi Tu8,
- Jing Chen
orcid.org/0000-0002-5376-90628,
- Jennifer Moliterno9,
- Murat Gunel
orcid.org/0000-0002-2290-70559,
- Lei Peng
orcid.org/0000-0001-7159-54411,2,3,9 na2 &
- …
- Sidi Chen
orcid.org/0000-0002-3819-50051,2,3,4,5,6,7,9,10,11,12 na2
Nature
(2026)Cite this article
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#### Subjects
- Applied immunology
- Cancer immunotherapy
- Immunotherapy
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 microenvironment1,2,3,4. 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.
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Fig. 1: In vivo CRISPRa and barcoded ORF screens identify OR7A10 as a booster for CAR-NK cell antitumour efficacy.
Fig. 2: OR7A10 ORF engineering enhances the antitumour function of CARPBNK cells.
Fig. 3: OR7A10 ORF engineering enhances metabolic fitness and resistance to TME-relevant immunosuppression of CAR-PBNK cells.
Fig. 4: OR7A10 ORF engineered CAR-PBNK cells show high in vivo antitumour efficacy and enhanced tumour infiltration across multiple tumour models.
Fig. 5: SCT reveals unbiased in vivo gene expression alterations driven by OR7A10 overexpression in tumour-infiltrating human primary CAR-NK cells.
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[Original source](https://www.nature.com/articles/s41586-026-10149-8)