Oxygen-generating cryogel vaccines help overcome tumor antigen tolerance and induce durable antitumor immunity in prostate cancer

Abstract Therapeutic cancer vaccines represent a promising approach to boost patients’ own immune system to fight cancer. However, many vaccine candidates have shown limited success in clinical trials in large part due to the insufficient antigen delivery to overcome tolerance and hypoxia mediated immunosuppressive mechanisms. Cryogel-based delivery scaffolds have emerged as a promising platform for cancer vaccines due to their biocompatibility and macroporous structure that allows for effective delivery to infiltrating antigen-presenting cells. However, these systems are limited by rapid, diffusion-mediated burst release of encapsulated recombinant proteins and local hypoxia-driven immunosuppression within the scaffold. Herein, we demonstrate that click conjugation of a tumor-associated protein within cryogel-based vaccines, combined with our new O 2 -generating platform (Click O 2 -Cryogel VAX ), helps overcome immune suppression and weak antigenicity and primes effective anti-cancer immune responses. Sustained antigen delivery promotes cellular memory and Th1-mediated anti-cancer responses. By reversing hypoxia-driven immunosuppression, O 2 acts as a powerful co-adjuvant to enhance humoral immunity. Together, Click O 2 -Cryogel VAX supports a robust antitumor response that inhibits tumor growth and prolongs survival in a therapeutic prostate cancer model. These findings support the further research and development of Click O 2 -Cryogel VAX as an effective delivery platform for therapeutic cancer vaccines.