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钙通道阻滞剂拉西地平通过重编程色氨酸代谢促进抗肿瘤免疫。

Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism.

作者信息

Sheng Yuwen, Qiao Chong, Zhang Zhonghui, Shi Xiaoke, Yang Linhan, Xi Ruiying, Yu Jialing, Liu Wanli, Zhang Guolin, Wang Fei

机构信息

Center for Natural Products Research, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, China.

School Of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 511400, China.

出版信息

Adv Sci (Weinh). 2025 Jan;12(3):e2409310. doi: 10.1002/advs.202409310. Epub 2024 Nov 25.

DOI:10.1002/advs.202409310
PMID:39585774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11744582/
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 (Ca1.2/1.3) 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.

摘要

钙通道功能障碍与某些癌症的发生和发展有关。然而，钙通道抑制剂在肿瘤免疫调节中的作用仍不清楚。在此，已确定钙通道阻滞剂拉西地平可有效抑制色氨酸代谢中的限速酶吲哚胺2,3-双加氧酶1（IDO1）的酶活性和表达。拉西地平激活效应T细胞并使调节性T细胞（Tregs）失能，通过将免疫“冷”肿瘤转变为“热”肿瘤来增强乳腺癌化疗药物的抗肿瘤作用。从机制上讲，拉西地平靶向钙通道（Ca1.2/1.3）以抑制Pyk2-JAK1-钙调蛋白复合物介导的IDO1转录抑制，从而抑制犬尿氨酸途径并通过调节NAD生物合成来维持总烟酰胺腺嘌呤二核苷酸（NAD）库。这些结果揭示了钙通道在肿瘤免疫中IDO1介导的色氨酸代谢中的新功能，并为拉西地平在乳腺癌代谢免疫治疗中的进一步开发提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/187b1de3d4fc/ADVS-12-2409310-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/15520d776ce6/ADVS-12-2409310-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/187b1de3d4fc/ADVS-12-2409310-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/46c8deb8e3be/ADVS-12-2409310-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/ae77fb5a8424/ADVS-12-2409310-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/c0127d640edb/ADVS-12-2409310-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/37c51fe807e5/ADVS-12-2409310-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/328b9301b56d/ADVS-12-2409310-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/61eeae534c45/ADVS-12-2409310-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/15520d776ce6/ADVS-12-2409310-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b577/11744582/187b1de3d4fc/ADVS-12-2409310-g008.jpg

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本文引用的文献

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Tryptophan metabolism in health and disease.色氨酸代谢与健康和疾病。
Cell Metab. 2023 Aug 8;35(8):1304-1326. doi: 10.1016/j.cmet.2023.06.004. Epub 2023 Jun 22.
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Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis.喹啉酸盐通过 NMDAR/PPARγ 信号轴促进胶质母细胞瘤中的巨噬细胞诱导免疫耐受。
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Current insight into the regulation of PD-L1 in cancer.当前对癌症中程序性死亡受体配体1（PD-L1）调控的见解。
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Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca channel function.Cavβ1 通过独立于电压门控钙通道功能调节 T 细胞的增殖和凋亡。
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Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses.IDO1 抑制剂治疗患者的卵巢肿瘤代谢适应性限制了抗肿瘤免疫反应。
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Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca ions and L-tryptophan.人钙敏感受体受钙离子和 L-色氨酸协同激活的结构机制。
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Regulation of PD-L1 expression in the tumor microenvironment.肿瘤微环境中 PD-L1 表达的调控。
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