Tumor cell-derived N-acetyl-aspartyl-glutamate reshapes the tumor microenvironment to facilitate breast cancer metastasis
Neurotransmitters are increasingly recognized to play important roles in limiting anti-tumor immunity. N-acetyl-aspartyl-glutamate (NAAG) has been extensively studied in neurological disorders; however, its potential role in restricting anti-tumor immunity has not been investigated. Here, we demonstrated that NAAG or its synthetase RimK-like family member B (RIMKLB) significantly disrupted anti-tumor immunity by rewiring the myeloid progenitor differentiation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which in turn promoted breast cancer growth and metastasis. Mechanistically, NAAG sustained the tumor immunosuppressive microenvironment by activating an NR2B-containing NMDA receptor (NR2B-NMDAR)-dependent p38-NOTCH1 axis, and subsequently stimulating tumor cell migration and invasion, as well as inducing PMN-MDSC differentiation and expansion. In mouse models, RIMKLB ablation or NMDAR inhibition enhanced the efficacy of anti-PD-1 therapy and suppressed tumor progression. An analysis of clinical samples revealed that high levels of NAAG and NR2B-NMDAR predicted a poor prognosis in TNBC patients. Collectively, our findings have uncovered a signaling role for tumor-derived NAAG beyond its classic function as a neurotransmitter that can be targeted pharmacologically to enhance immunotherapy against breast cancer.
Authors
- Jiahui Xu (ORCID: https://orcid.org/0000-0003-2780-2217)
- Juchuanli Tu (ORCID: https://orcid.org/0000-0003-2970-7256)
- Guohong Hu (ORCID: https://orcid.org/0000-0002-2980-5166)
- Yi‐Zhou Jiang (ORCID: https://orcid.org/0000-0003-3699-2630)
- Wucheng Zhu
- Siqin Li (ORCID: https://orcid.org/0009-0003-0161-8689)
- Ceshi Chen (ORCID: https://orcid.org/0000-0001-6398-3516)
- Haonan Dong (ORCID: https://orcid.org/0009-0008-2983-6377)
- Qiaodan Deng (ORCID: https://orcid.org/0009-0002-1792-8115)
- Jie Xia (ORCID: https://orcid.org/0000-0002-6586-0998)
- Suling Liu (ORCID: https://orcid.org/0000-0002-0475-0242)
- Wenzhao Liu (ORCID: https://orcid.org/0000-0001-7506-0663)
- Lixing Zhang (ORCID: https://orcid.org/0000-0002-8660-1370)
- W. F. Mader (ORCID: https://orcid.org/0000-0002-7344-998X)
- Xian Chen (ORCID: https://orcid.org/0000-0002-0731-8930)
- Yi Xiao (ORCID: https://orcid.org/0000-0002-9997-0394)
- Cuicui Liu (ORCID: https://orcid.org/0000-0002-5960-5851)
- Xilei Peng (ORCID: https://orcid.org/0009-0007-7734-3502)
- Xueyan He
- Xiu-Wu Bian
- Zhi-Ming Shao (ORCID: https://orcid.org/0000-0002-2487-0401)
Institutions
- Army Medical University (CN)
- Kunming Institute of Zoology (CN)
- Xiamen University (CN)
- Kunming Medical University (CN)
- Fudan University Shanghai Cancer Center (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Southwest Hospital (CN)
Publication Details
- Journal
- Science Bulletin
- Published
- 2024-12-27
- DOI
- https://doi.org/10.1016/j.scib.2024.12.039
- Citations
- 12
- Primary Topic
- Cancer, Stress, Anesthesia, and Immune Response
- Type
- article
- Field-Weighted Citation Impact
- 4.63