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Nature Immunology

Nature Immunology

IF: 27.6
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Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion

Published:4 January 2024 DOI:
Ronghui Yan, Pinggen Zhang, Shengqi Shen, Yu Zeng, Ting Wang, Zhaolin Chen, Wenhao Ma, Junru Feng, Caixia Suo, Tong Zhang, Haoran Wei, Zetan Jiang, Rui Chen, Shi-ting Li, Xiuying Zhong, Weidong Jia, Linchong Sun, Chunlei Cang, Huafeng Zhang, Ping Gao

Abstract

Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade. Carnosine is a mobile buffering metabolite. Here the authors link carnosine accumulation, hypoxia and intracellular pH homeostasis in cancer cells as a mechanism of tumor immune evasion via NFX1 degradation and galectin-9 activity.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
3-Iodobenzaldehyde[4-(diphenylamino)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]hydrazone 351986-85-1 C26H24IN7O 97 suppliers $27.00-$1850.00
3-Iodobenzaldehyde[4-(diphenylamino)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]hydrazone 351986-85-1 C26H24IN7O 97 suppliers $27.00-$1850.00
3-Iodobenzaldehyde[4-(diphenylamino)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]hydrazone 351986-85-1 C26H24IN7O 97 suppliers $27.00-$1850.00
3-Iodobenzaldehyde[4-(diphenylamino)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]hydrazone 351986-85-1 C26H24IN7O 97 suppliers $27.00-$1850.00

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