Hypoxia条件下的肿瘤细胞倾向于调节细胞外囊泡（EVs）的数量和内容以调节肿瘤微环境（TME），从而促进肿瘤进展。然而，Hypoxia如何影响EVs的分泌机制仍需进一步阐明。在此，我们证实头颈鳞状细胞癌（HNSCC）细胞在缺氧条件下增加了EVs的产生，缺氧使内质网衍生的EVs是主要受影响的亚型。在缺氧条件下，缺氧诱导因子1α（HIF-1α）的积累直接下调维持溶酶体稳态的ATP6V1A的表达。随后，受损的溶酶体降解导致多囊小体（MVBs）与溶酶体的融合减少，并使得其内部小囊泡（ILVs）分泌为EVs。这些发现建立了一个HIF-1α调节的溶酶体功能障碍-EV释放轴，并为更好地理解EV生物发生提供了精美的框架。©2023年作者。由Wiley期刊的Journal of Extracellular Vesicles代表国际细胞外囊泡协会出版。

Tumour cells under hypoxia tend to modulate the number and contents of extracellular vesicles (EVs) to regulate the tumour microenvironment (TME) and thus promote tumour progression. However, the mechanism of how hypoxia influences the secretion of EVs remains to be elucidated. Here, we confirm the increased production of EVs in head and neck squamous cell carcinoma (HNSCC) cells under hypoxia, where endosome-derived EVs are the main subtype affected by insufficient O2 . The accumulation of hypoxia-inducible factor-1α (HIF-1α) under hypoxia directly downregulates the expression of ATP6V1A, which is pivotal to maintain the homeostasis of lysosomes. Subsequently, impaired lysosomal degradation contributes to the reduced fusion of multivesicular bodies (MVBs) with lysosomes and enables the secretion of intraluminal vesicles (ILVs) as EVs. These findings establish a HIF-1α-regulated lysosomal dysfunction-EV release axis and provide an exquisite framework to better understand EV biogenesis.© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.