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

Therapeutic cancer vaccines represent a promising approach to boost patients' own immune system to fight cancer; however, they have shown limited success in clinical trials largely due to insufficient antigen delivery to overcome tolerance and hypoxia-mediated immunosuppression. Cryogel-based delivery scaffolds offer a promising platform for cancer vaccines due to their biocompatibility and macroporous structure, enabling effective delivery to infiltrating antigen-presenting cells. However, these systems are limited by rapid, diffusion-mediated burst release of encapsulated proteins and local hypoxia-driven immunosuppression. Click conjugation of a tumor-associated protein within cryogel-based vaccines, combined with an O2-generating platform (Click O2-CryogelVAX), overcomes immunosuppression and weak antigenicity, and primes effective antitumor immunity. Sustained antigen delivery promotes cellular memory and Th1-driven responses, while O2 release enhances humoral immunity. Together, Click O2-CryogelVAX supports a robust antitumor response and prolongs survival in a therapeutic prostate cancer model, supporting further investigation as an effective delivery platform for cancer vaccines.