<p>Tumor hypoxia represents one of the primary obstacle in effective cancer therapy by conferring drug resistance to chemotherapy, radiotherapy, and immunotherapy, and facilitating tumor growth and immune escape. The use of artificial oxygen carriers (AOCs) represents an innovative approach to overcoming hypoxia and improving therapeutic efficacy in oncology. Here, we review some of the most recent studies on various oxygen-carrying systems, such as hemoglobin-based oxygen carriers (HBOCs), perfluorocarbon-based therapeutic agents, oxygen-releasing biomaterials, and induced pluripotent stem cell-derived RBCs (iPSC-RBCs). Recent advancements, including hemoglobin modifications, encapsulation techniques, and bio-inspired oxygen carriers, have improved the stability, biocompatibility, and circulation time of these platforms. Preclinical evidence indicates that these therapies increase oxygen concentration in tumors and sensitize them to radiation therapy, chemotherapy, and immunotherapy. Nonetheless, several issues associated with the use of these therapies such as oxidative toxicity, nitric oxide scavenging, poor blood circulation time, production complications, and risks observed in earlier studies, still need to be addressed. In addition, while iPSC-derived RBCs could offer hope for future transfusion use, but their use against tumors has not been fully explored yet. In summary, artificial oxygen therapies represent an innovative treatment strategy for overcoming treatment resistance that results from hypoxia in cancer. However, further studies are required to optimize these technologies and evaluate their clinical potential. The next generation of oxygen therapies must prioritize safety, tumor specificity, and the integration of oxygen delivery with anticancer therapies.</p> Graphical Abstract <p>Schematic illustration depicting various artificial blood substitutes, such as hemoglobin-based oxygen carriers, perfluorocarbons, micro/nano bubbles, and stem cell-based oxygen delivery systems. This is done to address issues like anemia, blood shortage, and hypoxic resistance, among other factors that contribute to these problems.</p> <p></p>