Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism
Abstract Dysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202409310 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832593560541593600 |
|---|---|
| author | Yuwen Sheng Chong Qiao Zhonghui Zhang Xiaoke Shi Linhan Yang Ruiying Xi Jialing Yu Wanli Liu Guolin Zhang Fei Wang |
| author_facet | Yuwen Sheng Chong Qiao Zhonghui Zhang Xiaoke Shi Linhan Yang Ruiying Xi Jialing Yu Wanli Liu Guolin Zhang Fei Wang |
| author_sort | Yuwen Sheng |
| collection | DOAJ |
| description | Abstract Dysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3‐dioxygenase 1 (IDO1), a rate‐limiting enzyme in tryptophan metabolism. Lacidipine activates effector T cells and incapacitates regulatory T cells (Tregs) to augment the anti‐tumor effect of chemotherapeutic agents in breast cancer by converting immunologically “cold” into “hot” tumors. Mechanistically, lacidipine targets calcium channels (CaV1.2/1.3) to inhibit Pyk2‐JAK1‐calmodulin complex‐mediated IDO1 transcription suppression, which suppresses the kynurenine pathway and maintains the total nicotinamide adenine dinucleotide (NAD) pool by regulating NAD biosynthesis. These results reveal a new function of calcium channels in IDO1‐mediated tryptophan metabolism in tumor immunity and warrant further development of lacidipine for the metabolic immunotherapy in breast cancer. |
| format | Article |
| id | doaj-art-97cfca02b52b4dc2bf615bec01377828 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-97cfca02b52b4dc2bf615bec013778282025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202409310Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan MetabolismYuwen Sheng0Chong Qiao1Zhonghui Zhang2Xiaoke Shi3Linhan Yang4Ruiying Xi5Jialing Yu6Wanli Liu7Guolin Zhang8Fei Wang9Center for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaSchool Of Pharmaceutical Sciences Sun Yat‐Sen University Guangzhou 511400 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaState Key Laboratory of Membrane Biology School of Life Sciences Institute for Immunology Beijing Advanced Innovation Center for Structural Biology Beijing Key Lab for Immunological Research on Chronic Diseases Beijing 100084 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaCenter for Natural Products Research Chengdu Institute of Biology Chinese Academy of Sciences Chengdu 610041 ChinaAbstract Dysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3‐dioxygenase 1 (IDO1), a rate‐limiting enzyme in tryptophan metabolism. Lacidipine activates effector T cells and incapacitates regulatory T cells (Tregs) to augment the anti‐tumor effect of chemotherapeutic agents in breast cancer by converting immunologically “cold” into “hot” tumors. Mechanistically, lacidipine targets calcium channels (CaV1.2/1.3) to inhibit Pyk2‐JAK1‐calmodulin complex‐mediated IDO1 transcription suppression, which suppresses the kynurenine pathway and maintains the total nicotinamide adenine dinucleotide (NAD) pool by regulating NAD biosynthesis. These results reveal a new function of calcium channels in IDO1‐mediated tryptophan metabolism in tumor immunity and warrant further development of lacidipine for the metabolic immunotherapy in breast cancer.https://doi.org/10.1002/advs.202409310breast cancercalcium channelindoleamine 2, 3‐dioxygenaseimmunotherapylacidipine |
| spellingShingle | Yuwen Sheng Chong Qiao Zhonghui Zhang Xiaoke Shi Linhan Yang Ruiying Xi Jialing Yu Wanli Liu Guolin Zhang Fei Wang Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism Advanced Science breast cancer calcium channel indoleamine 2, 3‐dioxygenase immunotherapy lacidipine |
| title | Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism |
| title_full | Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism |
| title_fullStr | Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism |
| title_full_unstemmed | Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism |
| title_short | Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism |
| title_sort | calcium channel blocker lacidipine promotes antitumor immunity by reprogramming tryptophan metabolism |
| topic | breast cancer calcium channel indoleamine 2, 3‐dioxygenase immunotherapy lacidipine |
| url | https://doi.org/10.1002/advs.202409310 |
| work_keys_str_mv | AT yuwensheng calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT chongqiao calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT zhonghuizhang calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT xiaokeshi calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT linhanyang calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT ruiyingxi calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT jialingyu calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT wanliliu calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT guolinzhang calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism AT feiwang calciumchannelblockerlacidipinepromotesantitumorimmunitybyreprogrammingtryptophanmetabolism |