This study aims to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. Hypoxia is associated with poor prognosis in patients by conferring resistance to conventional therapies through various signaling pathways, including apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. The study discusses the capacity of oxygen-regulated transcription factor HIF-1 in modifying cancer sensitivity to therapeutic agents. Hypoxia-induced changes in gene expression and proteomics have significant effects on cellular and physiological functions, ultimately limiting patient prognosis. HIF-1α plays a crucial role in mediating hypoxia-induced signaling, which contributes to multiple steps of the therapeutic cascade. The study also explores the multifaceted interaction of HIFs with apoptosis, autophagy, DNA damage, mitochondrial activity, and p53 in the failure of HIF-mediated therapy. Finally, the study provides a comprehensive understanding of hypoxia-mediated molecular signaling pathways and suggests new directions for cancer therapy.This study aims to summarize the role of hypoxia in cancer therapy by regulating the tumor microenvironment (TME) and to highlight the potential of hypoxia-targeted therapy. Hypoxia is associated with poor prognosis in patients by conferring resistance to conventional therapies through various signaling pathways, including apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. The study discusses the capacity of oxygen-regulated transcription factor HIF-1 in modifying cancer sensitivity to therapeutic agents. Hypoxia-induced changes in gene expression and proteomics have significant effects on cellular and physiological functions, ultimately limiting patient prognosis. HIF-1α plays a crucial role in mediating hypoxia-induced signaling, which contributes to multiple steps of the therapeutic cascade. The study also explores the multifaceted interaction of HIFs with apoptosis, autophagy, DNA damage, mitochondrial activity, and p53 in the failure of HIF-mediated therapy. Finally, the study provides a comprehensive understanding of hypoxia-mediated molecular signaling pathways and suggests new directions for cancer therapy.