由于与肿瘤进展和转移相关的异常增殖和血管生成，缺氧是许多实体瘤的共同特征。大多数众所周知的缺氧效应是通过缺氧诱导因子（HIF）介导的。确定缺氧除了 HIF 引起的直接改变之外的长期影响，可以更好地理解缺氧驱动的转移和潜在的规避策略。在这里，我们发现了一种缺氧诱导的机制，可以发挥长期作用来促进转移。在乳腺癌患者来源的循环肿瘤细胞 (CTC) 系和常见乳腺癌细胞系中，缺氧通过 HIF-依赖和 HIF 独立机制。缺氧会在某些细胞类型中诱导持久的 IFN/AP 抑制，这种抑制在恢复正常含氧条件后仍持续存在，呈现出“缺氧记忆”表型。通过特异性低氧启动建立IFN/AP下调的低氧记忆，具有低氧记忆的细胞肿瘤发生和转移的能力增强。 IRF3 的过度表达增强了 IFN 信号传导，并在常氧条件下（而非低氧条件下）减少了肿瘤生长。组蛋白脱乙酰酶抑制剂 (HDACi) 恩替司他上调 IFN 靶点并消除缺氧记忆。这些结果指出了缺氧通过持久记忆促进肿瘤进展的机制，该记忆在转移级联过程中为 CTC 提供了优势。

Hypoxia is a common feature of many solid tumors due to aberrant proliferation and angiogenesis that is associated with tumor progression and metastasis. Most of the well-known hypoxia effects are mediated through hypoxia-inducible factors (HIFs). Identification of the long-lasting effects of hypoxia beyond the immediate HIF-induced alterations could provide a better understanding of hypoxia-driven metastasis and potential strategies to circumvent it. Here, we uncovered a hypoxia-induced mechanism that exerts a prolonged effect to promote metastasis. In breast cancer patient-derived circulating tumor cell (CTC) lines and common breast cancer cell lines, hypoxia downregulated tumor intrinsic type I interferon (IFN) signaling and its downstream antigen presentation (AP) machinery in luminal breast cancer cells, via both HIF-dependent and HIF-independent mechanisms. Hypoxia induced durable IFN/AP suppression in certain cell types that was sustained after returning to normoxic conditions, presenting a "hypoxic memory" phenotype. Hypoxic memory of IFN/AP downregulation was established by specific hypoxic priming, and cells with hypoxic memory had an enhanced ability for tumorigenesis and metastasis. Overexpression of IRF3 enhanced IFN signaling and reduced tumor growth in normoxic, but not hypoxic, conditions. The histone deacetylase inhibitor (HDACi) entinostat upregulated IFN targets and erased the hypoxic memory. These results point to a mechanism by which hypoxia facilitates tumor progression through a long-lasting memory that provides advantages for CTCs during the metastatic cascade.