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Volume 14
Issue 6
10.3390/biomedicines14061196
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal–Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer

by
Jiaxun Zhang
1,†,
Akezhouli Shahatiaili
1,†,
Yuhan Hou
1,†,
Ning Zhou
1,
Ke Huang
1,
Xiaojun Wang
2,
Dongmei Wang
3,
Zhentao Yu
4,
Xiaoli Feng
2 and
Yibo Gao
5,6,7,8,*
1
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2
Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3
Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
4
Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
5
Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
6
Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
7
State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
8
Department of Gastroenterology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan 030013, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Biomedicines 2026, 14(6), 1196; https://doi.org/10.3390/biomedicines14061196
Submission received: 25 March 2026 / Revised: 11 May 2026 / Accepted: 14 May 2026 / Published: 25 May 2026
(This article belongs to the Special Issue Advanced Research in Anticancer Inhibitors and Targeted Therapy)
Versions Notes

Abstract

Background: As the most lethal neuroendocrine tumor, small cell lung cancer (SCLC) can drive its progression by hijacking neuronal mechanisms. At the core of this neural integration is the N-methyl-D-aspartate receptor (NMDAR) complex. However, its pan-cancer expression and clinical significance in SCLC remain poorly understood. Methods: We characterized NMDAR transcriptomic profiles across human cancers to develop the NMDAscore, and analyzed three independent European and Asian SCLC cohorts to identify prognostic biomarkers. Furthermore, we investigated the molecular mechanisms of GRIN2A and evaluated the efficacy of GluN2 inhibitors. Results: The developed NMDAscore exhibited significant prognostic correlations in ACC, COAD, KIRC, UVM, KIRP, OV, PCPG, UCS, THCA, THYM, HNSC, KICH, LGG, and PAAD. Focusing on the SCLC cohorts, we identified GRIN2A (encoding the GluN2A subunit) as a statistically relevant prognostic biomarker associated with poor survival. Mechanistically, GRIN2A upregulation correlates with the activation of neuro-synaptic signaling, metabolic reprogramming, genomic instability, and an immune-cold microenvironment characterized by CD8+ T cell exclusion. Pharmacological inhibition of GluN2 using dizocilpine and the FDA-approved antagonist memantine suppressed SCLC proliferation and tumorigenicity in vitro, in 3D tumor spheroids and in vivo xenograft models. Conclusions: Collectively, these findings establish GRIN2A as a prognostic biomarker, linking synaptic hijacking, metabolic plasticity, immune evasion, and drug resistance, and identify the therapeutic potentials of the GluN2 inhibitors dizocilpine and memantine for SCLC.
Keywords: small cell lung cancer; NMDA receptor; GRIN2A; cancer neuroscience; tumor microenvironment; drug resistance small cell lung cancer; NMDA receptor; GRIN2A; cancer neuroscience; tumor microenvironment; drug resistance

Share and Cite

MDPI and ACS Style

Zhang, J.; Shahatiaili, A.; Hou, Y.; Zhou, N.; Huang, K.; Wang, X.; Wang, D.; Yu, Z.; Feng, X.; Gao, Y. Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal–Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer. Biomedicines 2026, 14, 1196. https://doi.org/10.3390/biomedicines14061196

AMA Style

Zhang J, Shahatiaili A, Hou Y, Zhou N, Huang K, Wang X, Wang D, Yu Z, Feng X, Gao Y. Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal–Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer. Biomedicines. 2026; 14(6):1196. https://doi.org/10.3390/biomedicines14061196

Chicago/Turabian Style

Zhang, Jiaxun, Akezhouli Shahatiaili, Yuhan Hou, Ning Zhou, Ke Huang, Xiaojun Wang, Dongmei Wang, Zhentao Yu, Xiaoli Feng, and Yibo Gao. 2026. "Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal–Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer" Biomedicines 14, no. 6: 1196. https://doi.org/10.3390/biomedicines14061196

APA Style

Zhang, J., Shahatiaili, A., Hou, Y., Zhou, N., Huang, K., Wang, X., Wang, D., Yu, Z., Feng, X., & Gao, Y. (2026). Pan-Cancer Prognostic Analysis of NMDAR Genes Discovered Therapeutic Implications of Neuronal–Cancer Crosstalk Mediator GRIN2A for Small Cell Lung Cancer. Biomedicines, 14(6), 1196. https://doi.org/10.3390/biomedicines14061196

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