TSC-mTORC1抑制介导的翻译重编程是许多压力情况下的主要适应机制，例如低氧、低ATP和低氨基酸。但癌细胞如何利用适应性途径在靶向糖酵解相关信号时在低乳酸压力下存活仍不确定。ETV4是一种癌基因转录因子，在人类肿瘤中经常发生失调。我们之前发现ETV4与非小细胞肺癌（NSCLC）的肿瘤进展和不良预后有关。在本研究中，我们报告了ETV4控制HK1表达和糖酵解-乳酸产生以激活mTORC1的发现。同时，我们也发现ETV4通过缓解TSC2对Rheb的抑制来增强mTORC1在NSCLC细胞中的活性。针对ETV4诱导的低乳酸压力是TSC2抑制mTORC1和全局蛋白质合成的重要输入，而核心压力颗粒成分G3BP2和HDAC6则有选择性地翻译。机制上，G3BP2招募溶酶体-TSC2来抑制mTORC1的活性。HDAC6脱乙酰化TSC2以维持其蛋白稳定性，并与G3BP2相结合以促进更多TSC2的招募来失活mTORC1。此外，HDAC6的微管逆向运输活性驱动聚集样近核mTOR分布，在压力下伴随较低的mTORC1活性。因此，在靶向ETV4时，HDAC6-G3BP2是促进溶酶体-TSC2并抑制mTORC1的关键复合物，可能代表了细胞在面对低乳酸挑战时的关键适应机制。

TSC-mTORC1 inhibition-mediated translational reprogramming is a major adaptation mechanism upon many stresses, such as low-oxygen, -ATP, and -amino acids. But how cancer cells hijack the adaptive pathway to survive under low-lactate stress when targeting glycolysis-related signaling remains uncertain. ETV4 is an oncogenic transcription factor frequently dysregulated in human cancer. We previously found that ETV4 is associated with tumor progression and poor prognosis in non-small cell lung cancer (NSCLC). In this study, we report that ETV4 controls HK1 expression and glycolysis-lactate production to activate mTORC1 by relieving TSC2 repression of Rheb in NSCLC cells. Targeting ETV4-induced low-lactate stress is an important input for TSC2 to inhibit mTORC1 and global protein synthesis, while the core stress granule components G3BP2 and HDAC6 are selectively translated. Mechanistically, G3BP2 recruits lysosomal-TSC2 to suppress mTORC1. HDAC6 deacetylates TSC2 to sustain protein stability and associates with G3BP2 to facilitate more recruiting of TSC2 to inactivate mTORC1. In addition, the microtubule retrograde transport activity of HDAC6 drives the aggregate-like perinuclear-mTOR distribution paralleled by lower mTORC1 activity under stress. Thus, HDAC6-G3BP2 is the key complex that promotes lysosomal-TSC2 and suppresses mTORC1 when targeting ETV4, which might represent a critical adaptive mechanism for cell survival under low-lactate challenges.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.