OX40–heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice

Although chimeric antigen receptor (CAR)-modified T cells have shown great success in treating B cell malignancies, they have demonstrated only limited efficacy against solid tumors. Here, we designed a CAR by integrating an antigen-independent OX40 that showed superior antitumor efficacy against multiple solid tumors. We unexpectedly found, through a CRISPR-Cas9-based whole-genome screen, that heparan sulfate is a ligand for OX40. We found that heparan sulfate can directly bind OX40 at the biochemical and cellular levels and that the interaction of heparan sulfate and OX40 activated the AKT, MAPK, and NF-κB signaling pathways. Functionally, the heparan sulfate-OX40 interaction enhanced cell adhesion and CAR T cell functional binding avidity to tumor cells. In vivo, OX40-expressing CAR T cells exhibited increased solid tumor infiltration and persistence dependent on the OX40-heparan sulfate interaction. Our findings provide insights into a glycan-costimulation interaction that is capable of regulating T cell immunity and has potential application in CAR T cell optimization.

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Publication Details

Journal
Science Translational Medicine
Published
2025-06-18
DOI
https://doi.org/10.1126/scitranslmed.adr2151
Citations
6
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
6.27
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article

OX40–heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice

Shun Lü, Enkhsaikhan Lkhagvasuren, Runbo Zhong, Ariunzaya Bat‐Erdene et al.
6 citations
Science Translational Medicine
CAR-T cell therapy research
6.27
article

OX40–heparan sulfate binding facilitates CAR T cell penetration into solid tumors in mice

Shun Lü, Enkhsaikhan Lkhagvasuren, Runbo Zhong, Ariunzaya Bat‐Erdene, Zekun Yu, Fanlin Li, Gansukh Choijilsuren, Tsogtsaikhan Sandag, Yue Huang, Xuanming Yang, Huihui Zhang, Junshi Zhang, Jie Liang, Wanting Wang, Hua Zhong
article en
6 citations

Abstract

Although chimeric antigen receptor (CAR)-modified T cells have shown great success in treating B cell malignancies, they have demonstrated only limited efficacy against solid tumors. Here, we designed a CAR by integrating an antigen-independent OX40 that showed superior antitumor efficacy against multiple solid tumors. We unexpectedly found, through a CRISPR-Cas9-based whole-genome screen, that heparan sulfate is a ligand for OX40. We found that heparan sulfate can directly bind OX40 at the biochemical and cellular levels and that the interaction of heparan sulfate and OX40 activated the AKT, MAPK, and NF-κB signaling pathways. Functionally, the heparan sulfate-OX40 interaction enhanced cell adhesion and CAR T cell functional binding avidity to tumor cells. In vivo, OX40-expressing CAR T cells exhibited increased solid tumor infiltration and persistence dependent on the OX40-heparan sulfate interaction. Our findings provide insights into a glycan-costimulation interaction that is capable of regulating T cell immunity and has potential application in CAR T cell optimization.

Science Translational MedicineVol. 17(803)
Shanghai Jiao Tong University (CN), Shanghai Chest Hospital (CN), Mongolian National University (MN), Mongolian National University of Medical Sciences (MN), Pudong New Area People's Hospital (CN)
Openalex Percentile: Top 3%
CAR-T cell therapy research
6.27
DOISourceOpenAlex
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