Hypoxia plays a critical role in cancer therapy by regulating the tumor microenvironment (TME). It contributes to therapy resistance through various signaling pathways, including apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. Hypoxia induces changes in gene expression and proteomic profiles, affecting cellular and physiological functions and limiting patient prognosis. Hypoxia promotes tumor progression, therapeutic resistance, and metastasis by altering the TME, increasing drug resistance, and promoting EMT. Hypoxia also leads to the formation of acidic TME, which enhances multidrug resistance (MDR) through mechanisms such as ion trapping, reduced apoptotic potential, and increased activity of multidrug transporters like P-gp. Hypoxia is associated with poor prognosis in cancer patients and is a key factor in the development of drug resistance. Hypoxia induces the expression of HIF-1α, which plays a central role in cellular responses to hypoxia. HIF-1α regulates the expression of genes involved in angiogenesis, glucose metabolism, and cell survival, contributing to tumor progression and resistance to chemotherapy. Hypoxia also affects immune responses by promoting immunosuppression and tumor resistance. Targeting hypoxia and HIFs may offer new strategies for overcoming therapy resistance in cancer. Hypoxia-mediated pathways, including autophagy, DNA damage repair, and mitochondrial dysfunction, are critical in cancer cell survival and resistance. Hypoxia can be targeted through various approaches, including hypoxia-activated prodrugs, gene therapy, and HIF inhibitors. These strategies aim to improve the efficacy of chemotherapy and overcome resistance in cancer patients. Future research should focus on understanding the complex interactions between hypoxia, HIFs, and cancer therapy to develop more effective treatment strategies.Hypoxia plays a critical role in cancer therapy by regulating the tumor microenvironment (TME). It contributes to therapy resistance through various signaling pathways, including apoptosis, autophagy, DNA damage, mitochondrial activity, p53, and drug efflux. Hypoxia induces changes in gene expression and proteomic profiles, affecting cellular and physiological functions and limiting patient prognosis. Hypoxia promotes tumor progression, therapeutic resistance, and metastasis by altering the TME, increasing drug resistance, and promoting EMT. Hypoxia also leads to the formation of acidic TME, which enhances multidrug resistance (MDR) through mechanisms such as ion trapping, reduced apoptotic potential, and increased activity of multidrug transporters like P-gp. Hypoxia is associated with poor prognosis in cancer patients and is a key factor in the development of drug resistance. Hypoxia induces the expression of HIF-1α, which plays a central role in cellular responses to hypoxia. HIF-1α regulates the expression of genes involved in angiogenesis, glucose metabolism, and cell survival, contributing to tumor progression and resistance to chemotherapy. Hypoxia also affects immune responses by promoting immunosuppression and tumor resistance. Targeting hypoxia and HIFs may offer new strategies for overcoming therapy resistance in cancer. Hypoxia-mediated pathways, including autophagy, DNA damage repair, and mitochondrial dysfunction, are critical in cancer cell survival and resistance. Hypoxia can be targeted through various approaches, including hypoxia-activated prodrugs, gene therapy, and HIF inhibitors. These strategies aim to improve the efficacy of chemotherapy and overcome resistance in cancer patients. Future research should focus on understanding the complex interactions between hypoxia, HIFs, and cancer therapy to develop more effective treatment strategies.