Protecting Against Postsurgery Oral Cancer Recurrence with an Implantable Hydrogel Vaccine for In Situ Photoimmunotherapy

Oral squamous cell carcinoma (OSCC) often recurs aggressively and metastasizes despite surgery and adjuvant therapy, driven by postoperative residual cancer cells near the primary tumor site. An implantable in situ vaccine hydrogel was designed to target residual OSCC cells post‐tumor removal. This hydrogel serves as a reservoir for the sustained localized release of δ‐aminolevulinic acid (δ‐ALA), enhancing protoporphyrin IX‐mediated photodynamic therapy (PDT), and a polydopamine‐hyaluronic acid composite for photothermal therapy (PTT). Additionally, immune adjuvants, including anti‐CD47 antibodies (aCD47) and CaCO3 nanoparticles, are directly released into the resected tumor bed. This approach induces apoptosis of residual OSCC cells through sequential near‐infrared irradiation, promoting calcium interference therapy (CIT). The hydrogel further stimulates immunogenic cell death (ICD), facilitating the polarization of tumor‐associated macrophages from the M2 to the M1 phenotype. This facilitates phagocytosis, dendritic cell activation, robust antigen presentation, and cytotoxic T lymphocyte‐mediated cytotoxicity. In murine OSCC models, the in situ vaccine effectively prevents local recurrence, inhibits orthotopic OSCC growth and pulmonary metastases, and provides long‐term protective immunity against tumor rechalle nge. These findings support postoperative in situ vaccination with a biocompatible hydrogel implant as a promising strategy to minimize residual tumor burden and reduce recurrence risk after OSCC resection. An implantable hydrogel‐based in situ vaccine provides localized phototherapy and immunotherapy to eliminate residual OSCC cells within the postsurgical cavity, while inducing robust systemic antitumor immunity through immunogenic cell death. By mimicking a personalized immunotherapy node capable of long‐term tunable drug release, this biomaterial‐mediated vaccine stimulates dendritic cell and cytotoxic T cell responses to suppress OSCC recurrence and distant metastasis.