Journal article
Ectopic NMDAR expression in cancer unmasks germline-encoded autoimmunity
- Abstract:
- Autoimmunity and anG-cancer immunity lie on the same biological conGnuum1,2 , but their link remains obscure. The paraneoplasGc neurological syndrome anG-NMDA receptor (NMDAR) encephaliGs (ANRE) is a paradigm for their connecGvity3 given that intratumoral NMDAR expression correlates with the generaGon of anG-NMDAR anGbodies . Here, we verify ectopic expression of GluN1 and GluN2B NMDAR sub-units in triple-negaGve breast cancer (TNBC) and model this using orthotopic TNBC tumors with inducible expression of GluN1-GluN2B NMDARs. We show that NMDAR expression is sufficient to induce B cell recruitment and their affinity maturaGon, consistent with an integrated adapGve immune response. ReconstrucGon of extended intratumoral B cell phylogenies and cryo-EM structural analyses demonstrated that affinity-matured hypermutated and class-switched anGbodies emerged from pre-exisGng germline-configuraGon lower-affinity anG-NMDAR anGbodies. DisGnct matured anGbodies targeted specific epitopes and induced conformaGonal rearrangements within the NMDAR amino-terminal domain, predicGve of their funcGonal effects, ranging from inhibiGon to potenGaGon. Passive transfer of an NMDAR-potenGaGng anGbody caused autonomic dysregulaGon and lowered the seizure threshold in healthy female mice, recapitulaGng key diagnosGc criteria of ANRE. We further idenGfy a correlaGon between intratumoral NMDAR expression and anG-NMDAR anGbody Gters in TNBC paGents. Taken together, our data establish a direct connecGon between intratumoral NMDAR expression, anGbody maturaGon, and the onset of autoimmunity. These findings suggest that germline-encoded anG-NMDAR anGbodies contribute to immune surveillance but can also trigger autoimmune disease upon maturaGon, revealing a mechanisGc tradeoff between cancer immunity and neurotoxicity.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 83.7MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-026-10278-0
Authors
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 104079/Z/14/Z
+ Medical Research Council
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- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- MR/V007173/1
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Publication date:
- 2026-03-25
- Acceptance date:
- 2026-02-13
- DOI:
- EISSN:
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1476-4687
- ISSN:
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0028-0836
- Language:
-
English
- Keywords:
- Pubs id:
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2372282
- Local pid:
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pubs:2372282
- Deposit date:
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2026-02-13
- ARK identifier:
Terms of use
- Copyright holder:
- Kleeman et al
- Copyright date:
- 2026
- Rights statement:
- © The Author(s) 2026. This article is licensed under a Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/.
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