Abstract: Hypoxia inducible factor (HIF) activates multiple downstream genes through transcription and regulates metabolic reprogramming of tumor cells, thus facilitating tumor cells to adapt to hypoxic stress. Under hypoxia, non-heme oxidases such as HIF-1 prolyl hydroxylase and catalase are depressed. Therefore, it is a new approach for cancer therapy to inhibit the immune escape during tumor progression or inhibit tumor HIF by using Mn-mimics of non-heme dioxygenase. In this article, the research progress in Mn-mimics of HIF prolyl hydroxylase, Mn-based nanozymes and nano-metalloenzyme-siRNA complexes for regulating HIF were reviewed, and the current problems and future development trend were also analyzed and prospected.