肿瘤的快速生长和血液供应不足导致微环境缺氧和营养匮乏。为了生存，肿瘤细胞需要忍受这些不利条件。在这里，我们发现 CD39 的表达在远离血管的坏死区域增强。我们推测这是肿瘤细胞主动适应恶劣环境的一种策略。进一步的研究表明，CD39是由营养剥夺通过AMPK信号通路诱导的。接下来我们探讨了 CD39 对于肿瘤细胞的意义。我们的结果表明，CD39 减少了细胞耗氧量，如果可用氧气有限，这对肿瘤细胞可能意义重大。代谢组学分析表明，CD39 的过度表达显着改变细胞代谢，并且三羧酸 (TCA) 循环被确定为受影响最大的代谢途径。为了探索其分子机制，我们进行了RNA-seq分析。结果显示，CD39显着上调丙酮酸脱氢酶激酶同工酶2（PDK2）的表达，从而抑制丙酮酸脱氢酶（PDH）和TCA循环的活性。最后，CD39被证明可以保护肿瘤细胞免受缺氧诱导的细胞死亡并降低瘤内缺氧水平。 CD39作为近年来新发现的免疫检查点分子引起了广泛关注。我们的研究结果表明CD39不仅在免疫调节中发挥作用，而且还可以通过抑制TCA循环和减少细胞耗氧量使肿瘤细胞耐受缺氧。这项研究提供的证据表明，靶向 CD39 可能是一种防止肿瘤细胞在应激条件下适应的新策略。版权所有 © 2024 Elsevier Inc. 保留所有权利。

Rapid tumor growth and insufficient blood supply leads to the development of a hypoxic and nutrient deprived microenvironment. To survive, tumor cells need to tolerate these adverse conditions. Here we found the expression of CD39 was enhanced in necrotic regions distant from blood vessels. We speculate that this is a strategy for tumor cells to actively adapt to the hostile environment. Further studies showed that CD39 was induced by nutrient deprivation through the AMPK signalling pathway. We next explored the significance of CD39 for tumor cells. Our results showed that CD39 reduced cellular oxygen consumption, which could be significant for tumor cells if the available oxygen is limited. Metabolomics analysis showed that overexpression of CD39 significantly altered cellular metabolism, and tricarboxylic acid (TCA) cycle was identified as the most impacted metabolic pathway. In order to explore the molecular mechanism, we performed RNA-seq analysis. The results showed that CD39 significantly up-regulated the expression of pyruvate dehydrogenase kinase isozyme 2 (PDK2), thus inhibiting the activity of pyruvate dehydrogenase (PDH) and TCA cycle. Finally, CD39 was shown to protect tumor cells from hypoxia-induced cell death and reduce intratumoral hypoxia levels. CD39 has attracted a great deal of attention as a newly discovered immune checkpoint molecule in recent years. Our results indicate that CD39 not only plays a role in immune regulation, but also enables tumor cells to tolerate hypoxia by inhibiting TCA cycle and reducing cellular oxygen consumption. This study provides evidence that targeting CD39 may be a novel strategy to prevent adaptation of tumor cells in stressed conditions.Copyright © 2024 Elsevier Inc. All rights reserved.