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.
摘要：
肿瘤细胞和周围的免疫细胞经历代谢重编程，导致酸性肿瘤微环境。然而,目前尚不清楚肿瘤细胞在肿瘤进展过程中如何适应这种酸性应激.这里我们展示了肌肽，一种在肿瘤细胞缺氧下积累的流动缓冲代谢物，调节细胞内pH稳态并驱动溶酶体依赖性肿瘤免疫逃避。以前未被识别的肌肽合成酶的同工型，CARNS2促进缺氧下肌肽合成。肌肽通过充当可移动的质子载体以加速细胞溶质H的流动性和释放来维持细胞内pH（pHi）稳态，进而控制溶酶体亚细胞分布，酸化和活性。此外，通过维持溶酶体活性，肌肽促进核转录因子X-box结合1（NFX1）降解，引发半乳糖凝集素-9和T细胞介导的免疫逃逸和肿瘤发生。这些发现表明了癌细胞中pHi调节的非常规机制，并证明了溶酶体如何促进免疫逃避。从而为开发针对肝细胞癌的联合治疗策略提供了基础，该策略利用免疫检查点阻断破坏的pHi稳态。
