Project Summary Overcoming the poor efficacy of tumor cell vaccines will require enhancing activation of the immune system and preventing an immunosuppressive tumor microenvironment such as local hypoxia. In this proposal, we will address this critical need by engineering tumor cell vaccines with advanced oxygen-releasing biomaterials (O2- cryogels) to combat hypoxia-driven immunosuppression and improve antitumor immune responses in relevant mouse models of prostate cancer. Our preliminary data in mice indicate that: (i) O2-cryogels can reverse local hypoxia and restore the function of key immune cells (dendritic cells; DCs); (ii) once in the body, cryogel vaccines efficiently localize transplanted tumor cells, controllably release immunomodulatory factors, and recruit large numbers of DCs from the host; and (iii) elicit a specific and robust vaccine-induced T cell-mediated antitumor immunity. Here, we will optimize the characteristics of O2-cryogels for maximum antitumor efficacy and safety; and assess their ability to suppress the local hypoxic stress and improve DC recruitment, activation, and homing to the draining lymph nodes. Finally, we will test O2-cryogel vaccines in prophylactic and therapeutic mouse models of prostate cancer to determine their ability to induce specific, effective, and long-lasting antitumor immune responses. This proposal may have a sustained impact on the field by defining a new avenue of cancer immunotherapy that operates independently but synergizes with other therapies.