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Inhibition of glycosphingolipid synthesis overcomes the steric hindrance of CD30 N-glycans to augment CD30-targeted immunotherapeutic efficacy

Cellular & Molecular Immunology (2026) Cite this article

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Abstract

CD30-targeted chimeric antigen receptor (CAR) T-cell therapy faces clinical challenges in classical Hodgkin lymphoma (cHL). While current optimization strategies focus on CAR design, manufacturing protocols, and preconditioning regimens, tumor-intrinsic resistance mechanisms remain poorly understood. Our study revealed that CD30 in cHL cells is associated with N-glycans at Asn101 and Asn276, which are essential for protein stability but do not affect cell proliferation or apoptosis. Genetic ablation of these N-glycans or enzymatic deglycosylation significantly enhanced CD30-targeted CAR-T-cell accessibility to tumor cells, leading to improved T-cell activation and cytotoxic function. Notably, pretreatment with eliglustat, an FDA-approved glycosphingolipid synthesis inhibitor, selectively potentiated the antitumor activity of CD30-targeted CAR-T cells in wild-type CD30-expressing tumors but had minimal effects on CD30 glycosylation-deficient variants. Eliglustat combined with CD30-targeted CAR-T cells resulted in superior tumor control in xenograft models without additional toxicity. Mechanistically, eliglustat trimmed terminal sialic acids from CD30 N-glycans while preserving the core N-glycan structure. Furthermore, the addition of eliglustat also enhanced the tumor-killing activity of brentuximab vedotin (BV), a CD30-directed antibody–drug conjugate, both in vitro and in vivo. This glycoimmunotherapy paradigm represents a clinically actionable approach to overcome glycan-mediated immune evasion and enhance therapeutic efficacy in CD30-positive lymphomas.

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All the data and materials related to this study are available from the corresponding author upon request.

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Acknowledgements

We thank all of the members of the Department of Biotherapy for their discussion and support.

Funding

This work was supported by the National Science and Technology Major Project (2023ZD0501303) and the National Natural Science Foundation of China (Nos. 92578101 and 82370228).

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Author notes

  1. These authors contributed equally: Yuting Pan, Yixin Chang.

  2. These authors jointly supervised this work: Jing Nie, Weidong Han.

Authors and Affiliations

  1. Department of Biotherapy, The First Medical Centre, Chinese People’s Liberation Army General Hospital, Beijing, China

    Yuting Pan, Yixin Chang, Xueting Qin, Chunmeng Wang, Nannan Lu, Jing Nie & Weidong Han

  2. Medical School of Chinese People’s Liberation Army, Beijing, China

    Yuting Pan

  3. Beijing Proteome Research Center, Beijing, China

    Wanjun Zhang

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Contributions

WH and JN designed the research; YP and YC performed the experiments and analyzed the data; CW, XZ, XQ and NL assisted with the experiments. YP and JN wrote the manuscript.

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Correspondence to Jing Nie or Weidong Han.

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The authors declare that they have no competing interests. WH is an editorial board member of Cellular & Molecular Immunology, but he has not been involved in the peer review or the decision-making of the article.

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Pan, Y., Chang, Y., Zhang, W. et al. Inhibition of glycosphingolipid synthesis overcomes the steric hindrance of CD30 N-glycans to augment CD30-targeted immunotherapeutic efficacy. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01421-y

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