Photoimmunological hydrogel vaccine creates a supportive immune niche to promote antigen cross-presentation cascade and cancer-immunity cycle progression

Therapeutic tumor vaccines have emerged as promising weapons for inducing robust and durable antitumor immune responses, demonstrating substantial potential for cancer treatment. However, clinical efficacy is significantly hindered by tumor immunogenicity scarcity, antigen presentation deficiency, and immunosuppressive tumor microenvironment. To surmount these obstacles, we proposed an injectable photoimmunological hydrogel vaccine (CRPO/G@ALG) to improve immunotherapy outcomes through the dual mechanism of immunogenic cell death (ICD) induction and dendritic cell (DC) recruitment. The model antigen ovalbumin (OVA) and toll-like receptor 7/8 agonist resiquimod (R848) were incorporated into photothermal copper sulfide nanoparticles (CuS) to construct the nanovaccine CRPO, which was subsequently encapsulated with the granulocyte-macrophage colony-stimulating factor (GM-CSF) in sodium alginate (ALG) to form the hydrogel vaccine CRPO/G@ALG. Following peritumoral administration, CRPO/G@ALG undergoes gelation in response to physiological calcium ions, facilitating the localized retention and controlled release of payloads. Near-infrared (NIR) irradiation triggers ICD in tumor cells, generating an <i>in situ</i> antigen reservoir enriched with tumor-associated antigens (TAAs) to bolster tumor immunogenicity. Concurrently, GM-CSF attracts DCs to infiltrate tumor tissues, while R848 promotes DC maturation and antigen cross-presentation. These synergistic effects prolong the duration of immune stimulation and expand both the breadth and depth of antitumor immunity. In 4T1 tumor-bearing mice, CRPO/G@ALG effectively suppressed primary and distant tumor growth and markedly reduced lung metastasis. Collectively, our findings illustrate the transformative potential of integrating ICD induction, DC recruitment, and hydrogel delivery systems, offering new avenues to advance therapeutic tumor vaccine applications.