Hypoxia and oxidative stress are key features of solid tumors, with hypoxia-inducible factors (HIFs) and nuclear factor erythroid 2-related factor 2 (NRF2) playing critical roles in tumor growth and progression. HIFs, including HIF-1α and HIF-2α, respond to low oxygen levels by activating genes that increase oxygen supply and reduce consumption. NRF2, on the other hand, responds to oxidative stress by activating genes that remove oxidants and promote cell survival. Both HIFs and NRF2 are involved in tumor progression, and their interplay is complex, with HIFs and NRF2 often working together or in opposition to influence cancer development. HIFs are regulated by the von Hippel-Lindau (pVHL) protein and prolyl hydroxylase domain (PHD) proteins, which hydroxylate HIF-α subunits under normal oxygen conditions, leading to their degradation. Under hypoxia, PHD activity is inhibited, allowing HIF-α to accumulate and translocate to the nucleus, where it dimerizes with HIF-β to activate genes involved in angiogenesis, metabolism, and cell survival. NRF2 is regulated by KEAP1, with oxidative stress causing KEAP1 to release NRF2, allowing it to translocate to the nucleus and activate genes involved in antioxidant defense and cell survival. HIFs and NRF2 are closely linked in cancer, with their activities often interdependent. For example, NRF2 can enhance HIF-1α expression, promoting tumor growth, while HIF-1α can stabilize NRF2, enhancing its activity. However, their relationship can also be antagonistic, with HIF-1α inhibiting NRF2 activity in some contexts. Both HIFs and NRF2 are involved in cancer progression, including tumor angiogenesis, EMT, metastasis, and cancer stem cell (CSC) traits. Their dysregulation contributes to therapeutic resistance and poor patient outcomes. Understanding the complex interactions between HIFs and NRF2 is crucial for developing new cancer therapies.Hypoxia and oxidative stress are key features of solid tumors, with hypoxia-inducible factors (HIFs) and nuclear factor erythroid 2-related factor 2 (NRF2) playing critical roles in tumor growth and progression. HIFs, including HIF-1α and HIF-2α, respond to low oxygen levels by activating genes that increase oxygen supply and reduce consumption. NRF2, on the other hand, responds to oxidative stress by activating genes that remove oxidants and promote cell survival. Both HIFs and NRF2 are involved in tumor progression, and their interplay is complex, with HIFs and NRF2 often working together or in opposition to influence cancer development. HIFs are regulated by the von Hippel-Lindau (pVHL) protein and prolyl hydroxylase domain (PHD) proteins, which hydroxylate HIF-α subunits under normal oxygen conditions, leading to their degradation. Under hypoxia, PHD activity is inhibited, allowing HIF-α to accumulate and translocate to the nucleus, where it dimerizes with HIF-β to activate genes involved in angiogenesis, metabolism, and cell survival. NRF2 is regulated by KEAP1, with oxidative stress causing KEAP1 to release NRF2, allowing it to translocate to the nucleus and activate genes involved in antioxidant defense and cell survival. HIFs and NRF2 are closely linked in cancer, with their activities often interdependent. For example, NRF2 can enhance HIF-1α expression, promoting tumor growth, while HIF-1α can stabilize NRF2, enhancing its activity. However, their relationship can also be antagonistic, with HIF-1α inhibiting NRF2 activity in some contexts. Both HIFs and NRF2 are involved in cancer progression, including tumor angiogenesis, EMT, metastasis, and cancer stem cell (CSC) traits. Their dysregulation contributes to therapeutic resistance and poor patient outcomes. Understanding the complex interactions between HIFs and NRF2 is crucial for developing new cancer therapies.