All figures were created with BioRender

All figures were created with BioRender.com. Funding This work was supported by NIH U54 “type”:”entrez-nucleotide”,”attrs”:”text”:”CA210181″,”term_id”:”35253228″,”term_text”:”CA210181″CA210181 (Project 2), R01 CA243577 and the Effie Marie Cain Fellowship to RAB. Institutional Review Board Statement Not applicable. Informed Consent Statement Not applicable. Data Availability Statement Not applicable. Conflicts of Interest The authors declare no conflict of interest. Footnotes Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.. limitation of hypoxia-targeted therapies. We believe, with comprehensive WQ 2743 knowledge of hypoxia in the tumor microenvironment, challenges of hypoxia-targeted therapies might be better understood and addressed. Abstract Hypoxia is a well-known characteristic of solid tumors that contributes to tumor progression and metastasis. Oxygen deprivation due to high demand of proliferating cancer cells WQ 2743 and standard of care therapies induce hypoxia. Hypoxia signaling, mainly mediated by the hypoxia-inducible transcription factor (HIF) family, results in tumor cell migration, proliferation, metabolic changes, and resistance to therapy. Additionally, the hypoxic tumor microenvironment impacts multiple cellular and non-cellular compartments in the tumor stroma, including disordered tumor vasculature, homeostasis of ECM. Hypoxia also has a multifaceted and often contradictory influence on immune cell function, which contributes to an immunosuppressive environment. Here, we review the important function of HIF in tumor stromal components and summarize current clinical trials targeting hypoxia. We provide an overview of hypoxia signaling in tumor stroma that might help address some of the challenges associated with hypoxia-targeted therapies. promoter as well as promoters of rate-limiting glycolytic genes and em LDHA /em , which lead to elevated transcript and protein levels and contribute to enhanced glycolytic activity of CAFs derived from breast WQ 2743 cancer patients [58]. Furthermore, hypoxic mammary CAFs derived from triple-negative breast cancer patients promote angiogenesis and abnormal vessel formation in a CAF-endothelial cell co-culture system [59]. On the contrary, loss of HIF-1 specifically in FSP1+ CAFs was found to accelerate mammary tumor growth and also contribute to decreased tumor vessel density [60]. In addition, global PHD2 haplodeficiency was reported to decrease CAF activation and impair CAF migration and ECM deposition, which reduced metastasis in a spontaneous MMTV-PyMT breast cancer model [31]. Interestingly, the effect on CAF activity relies on PHD2 deletion on tumor cells, but not on CAFs as PHD2 deficiency in platelet-derived growth factor receptor (PDGFR)-positive CAFs does not influence metastasis [31]. However, another study provided evidence that depletion of PHD2 in human head and neck CAFs phenocopies the response to hypoxia in a 3D collagen I/Matrigel culture system [61]. Furthermore, a pan-PHD inhibitor (DMOG) reduces WQ 2743 tumor stiffness and metastasis in mice bearing 4T1 breast cancer. Interestingly, this WQ 2743 efficacy appears to be achieved by targeting PHD2 in CAFs [61]. These contradictory results highlight the complexity and heterogeneity of CAF biology. In Rplp1 general, the hypoxic tumor microenvironment directly effects collagen deposition and ECM remodeling mainly through HIF activity, which typically enhances tumor progression and metastasis. However, the functions of HIF-1 and HIF signaling in CAFs are more complicated given the heterogeneity of CAF subpopulations, which likely contributes to the seemingly contradictory findings regarding CAF biology and hypoxia. 4. The Effect of Hypoxia on T Cells Hypoxia has direct and complex effects on tumor-infiltrating T cells, including different subtypes of CD4+ T helper cells and CD8+ effector T cells, potentially resulting in reduced efficacy of immunotherapies. 4.1. CD4+ T Helper Cells and Regulatory T Cells There are several subtypes of CD4+ T cells, due to divergent differentiation of na?ve progenitor cells in response to different cytokine stimuli. The most commonly studied CD4+ T cells in the immune response to cancer are T helper (Th)1, Th2, Th17, and regulatory T cell (Treg) [62]. Th1 cells characterized by secreting stimulatory cytokines IFN- and TNF- are considered as proinflammatory and they prime CD8+ T cells and are responsible for driving an immune response against tumor cells or infection [63]. While Th2 and Th17 cells may promote tumor growth through expression of immunosuppressive cytokines including IL-4, IL-5, IL-13, and IL-17A, although the contribution of these cells to the tumor immune landscape is not completely clear [62,64,65,66,67,68]. CD4+ Tregs are characterized by transcription factor FoxP3 expression and are predominantly immunosuppressive. Tregs maintain peripheral tolerance under normal conditions. The recruitment and expansion of Tregs is enhanced in most tumors and typically impedes antitumor activity of effector cells [69]. Continuous stimulation of the T cell receptor (TCR) under normoxic conditions induces HIF-1 expression through PI3K/mTOR signaling [70,71]. However, hypoxia in tumors can elevate HIF-1.