The contribution of the TME in the progress of the malignant tumor is significant and now also increasingly recognized to affect the efficiencies of drug delivery and distribution within tumors. [8] Hypoxia is the phenomenon where the oxygen supplied through the usually aberrant tumor blood vessels are insufficient to consistently meet the growing tumor's metabolic needs. [9] Hypoxia occurs in tumors due to insufficient oxygen supply in relation to the tumors' metabolism and includes: a) acute hypoxia, the result of poor blood perfusion caused by abnormal, aberrant vasculature, giving rise to tortuous network organization, irregular flow pattern, [4] and b) chronic hypoxia, the cause and the result of a sparse vascular density in the tumor, giving rise to insufficient oxygen delivered to tumor cells spatially distant from blood vessels. Compensatory angiogenesis itself is also regarded as the result of mainly nutrient and oxygen deprivation as the tumor grows. [10] Hence, hypoxia is an element in the TME that is closely interconnected with pathological angiogenesis and extracellular matrix in cancer. In general, cells are sensitive to low oxygen conditions, which activate the hypoxia-inducible factor (HIF) family of transcriptional factors to allow for expression of genes that may enhance tumor survival under the hypoxic environment. One consequential outcome is the accumulation of vascular endothelial growth factor (VEGF) under transcription by HIF-1α, resulting in the induction of angiogenesis. [11] Under hypoxia, the oxygen-dependent subunit of HIF-1, HIF-1α, is successfully accumulated (otherwise degraded in normoxic conditions) to dimerize with an oxygen-independent subunit to form the HIF-1 dimer. [4] HIF-1 then upregulates dozens of genes that allows for both adaptation and long-term expansion of the tumor cells. [12] Hypoxia is a critical factor to examine, as there is increasing recognition of its role as a potential target during cancer therapy, although the dual role of HIFs in both promoting survival and apoptosis poses a challenge for certain tumor types and cases. [13] 1.2. Hypoxia Aggravates the Challenges for Cancer Therapy A major consequence of hypoxia is the occurrence of hypoxiainduced metastasis. Hypoxia and metastasis have been Anti-hypoxia cancer nanomedicine (AHCN) holds exciting potential in improving oxygen-dependent therapeutic efficiencies of malignant tumors. However, most studies regarding AHCN focus on optimizing structure and function of nanomaterials with presupposed successful entry into tumor cells. From such a traditional perspective, the main barrier that AHCN needs to overcome is mainly the tumor cell membrane. However, such an oversimplified perspective would neglect that real tumors have many biological, physiological, physical, and chemical defenses preventing the current state-of-the-art AHCNs from even reaching the targeted tumor cells. Fortunately, in recent years, some studies are beginning to intentionally focus on overcoming physiological barriers to alleviate hypoxi...