Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors
文献类型：期刊论文
| 作者 | Yang, Ruirui7,8,9; Wang, Bei6; Su, Zhaoming6; Song, Ying6; Zhang, Yingying5,8; Liu, Yadan6,7,8; Zhang, Yinghui7,8; He, Changyu4; Yang, Xi3; Zhong, Feisheng7,8 |
| 刊名 | SCIENCE TRANSLATIONAL MEDICINE
 |
| 出版日期 | 2025-06-04 |
| 卷号 | 17期号:801页码:18 |
| ISSN号 | 1946-6234 |
| DOI | 10.1126/scitranslmed.adn6921 |
| 英文摘要 | Low-dose methotrexate (MTX) is the first-line drug for treating rheumatoid arthritis as an immunosuppressor. We have identified that low-dose MTX exhibits antitumor immune activity. MTX treatment reduced tumor metastasis and enhanced the efficacy of radiation therapy and immune checkpoint blockade therapy in mice. Mechanistically, MTX selectively induced DNA damage, cGAS-STING [cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS)-stimulator of interferon genes (STING)] pathway activation, and cGAMP generation in cancer cells. Furthermore, MTX bound to the substrate-binding pocket of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), inhibiting ENPP1-mediated cGAMP hydrolysis and adenosine generation. Consequently, MTX reduced extracellular adenosine and enhanced host STING-mediated antitumor immunity. In addition, a preliminary clinical trial demonstrated promising efficacy and safety of low-dose MTX in combination with immunotherapy and radiotherapy for patients with unresectable or metastatic solid tumors, showing improved outcomes compared with historical controls. These results highlight the previously unrecognized immunostimulatory functions of MTX and provide a rationale for combining MTX with tumor immunotherapy and radiotherapy in clinical settings. |
| WOS关键词 | REGULATORY T-CELLS ; POTENT INHIBITORS ; CANCER ; DERIVATIVES ; ADENOSINE ; CGAMP ; ENPP1 ; MINERALIZATION ; RADIOTHERAPY ; INFLAMMATION |
| 资助项目 | National Natural Science Foundation of China[T2225002] ; National Natural Science Foundation of China[82273855] ; National Natural Science Foundation of China[82304379] ; National Natural Science Foundation of China[82474143] ; National Key Research and Development Program of China[2023YFC2305904] ; National Key Research and Development Program of China[2022YFC3400504] ; Strategic Priority Research Program of the Chinese Academy of sciences[XDB0830200] ; Youth Innovation Promotion Association CAS[2023296] ; Natural Science Foundation of Shanghai[22ZR1474300] ; Young Elite Scientists Sponsorship Program by CAST[2023QNRC001] ; SIMM-SHUTCM Traditional Chinese Medicine Innovation Joint Research Program[E2G805H] ; Project of Jiangsu Provincial Health Commission[Z2022016] |
| WOS研究方向 | Cell Biology ; Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001501589400005 |
| 出版者 | AMER ASSOC ADVANCEMENT SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318255]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Geng, Wei; Zhang, Sulin; Zheng, Mingyue |
| 作者单位 | 1.Nanjing Univ, Yancheng 1 Peoples Hosp, Affiliated Hosp, Med Sch, 66 South Peoples Rd, Yancheng 224000, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 3.Fudan Univ, Shanghai Canc Ctr, Shanghai Med Coll, Dept Radiat Oncol, Shanghai 200032, Peoples R China 4.Shanghai Jiao Tong Univ, Ruijin Hosp, Shanghai Inst Digest Surg, Dept Surg,Sch Med,Shanghai Key Lab Gastr Neoplasms, Shanghai 200025, Peoples R China 5.Univ Sci & Technol China, Div Life Sci & Med, 443 Huangshan Rd, Hefei 230026, Anhui, Peoples R China 6.Nanjing Univ Chinese Med, Sch Chinese Mat Med, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 7.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 8.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 9.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, 1 Sub Lane Xiangshan, Hangzhou 310024, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yang, Ruirui,Wang, Bei,Su, Zhaoming,et al. Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors[J]. SCIENCE TRANSLATIONAL MEDICINE,2025,17(801):18. |
| APA | Yang, Ruirui.,Wang, Bei.,Su, Zhaoming.,Song, Ying.,Zhang, Yingying.,...&Zheng, Mingyue.(2025).Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors.SCIENCE TRANSLATIONAL MEDICINE,17(801),18. |
| MLA | Yang, Ruirui,et al."Methotrexate exerts antitumor immune activity and improves the clinical efficacy of immunotherapy in patients with solid tumors".SCIENCE TRANSLATIONAL MEDICINE 17.801(2025):18. |
入库方式： OAI收割
来源：上海药物研究所
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