Chemotherapy is a paramount clinical technique in the treatment of the medium and advanced cancer. However, it faces challenges in achieving high specificity, leading to the potential severe side effects in patients as a result of their non-selective interaction with both cancerous and healthy cells. Additionally, the limited ability of chemical drugs to accumulate at the tumor site results in a decrease in the efficacy of chemotherapy. In order to tackle this challenge, a range of prodrugs have been innovatively crafted and tailored by exploiting the unique tumor microenvironment, including hypoxia, low pH, high levels of reactive oxygen species (ROS) and overexpressed enzymes, to specifically eradicate tumor cells. As a typical feature of solid tumor, hypoxia has been identified as a critical target for prodrug molecular design, which arises from the imbalance between increased oxygen consumption due to rapid tumor cell proliferation and inadequate oxygen supply resulting from limited neovascularization. Hypoxia is also correlated with enhanced tumor invasiveness, metastasis, heightened resistance to radiotherapy. Furthermore, it often exhibits significantly stronger reducibility compared to normoxic cells in hypoxic tumors because of the overexpression of reductases. To now, two strategies are applied to construct hypoxia-responsive prodrugs. One is the hypoxia-sensitive bio-reductive prodrug. This type of prodrug is nontoxic in nature and it can only be activated by specific overexpressed enzymes in hypoxic tumor microenvironment. Subsequently, it is transformed into cytotoxic drugs, like tirapazamine and banoxantrone. The other method is to construct hypoxiaactivated prodrugs by coupling drugs with photosensitizers or other molecules through hypoxia-responsive chemical bonds. Upon activation in hypoxic condition, the active drugs can be released by breaking the sensitive bonds in prodrugs. In contrast to type one, the latter allows for easier attainment of high drug-loading content and improved loading stability.