Extracellular Matrix Scaffold-Assisted Tumor Vaccines Induce Tumor Regression and Long-Term Immune Memory

Materials that interact with biological systems have been engineered for biomedical applications. These biomaterials have revolutionized cancer care by enabling targeted and sustained drug delivery, reducing side effects, promoting tissue regeneration and recovery. However, every implanted biomaterial triggers a spectrum of host immune responses that depend on its composition and architecture, ultimately affecting its function. Extracellular matrix (ECM) scaffolds derived from decellularized mammalian tissues are implanted in patients to surgically reconstruct damaged tissues following tumor resection. These scaffolds initiate a Type 2 immune response driven by the IL-4 cytokine, promoting scaffold remodeling and tissue regeneration. While previous studies have explored the use of ECM scaffolds in cancer care, a few have investigated their potential as delivery platforms for cancer vaccines, particularly in inducing cytotoxic immunity. In this study, we developed an injectable cancer vaccine using an ECM scaffold made from decellularized small intestinal submucosa (SIS). We screened cancer vaccine adjuvants for co-delivery with an ECM scaffold by subcutaneous implantation in mice, and it was discovered that a molecule called cyclic di-AMP, which activates the STING pathway, was the most effective at triggering a strong immune response without interfering with healing processes that rely on interleukin 4 (IL-4). The use of the ECM scaffold significantly enhanced therapeutic vaccine efficacy, curing 50–75% of lymphoma tumors in mice, while no tumors were cured with the soluble vaccine without the scaffold. SIS-ECM scaffold-assisted vaccination generated long-term antigen-specific memory, producing 4-fold effector memory CD8+ T cells (Tem) in response to tumor challenge compared to untreated controls. In conclusion, ECM scaffolds are a promising delivery system for cancer vaccines. They enhance vaccine effectiveness while preserving the immune response needed for tissue repair, offering potential for localized immunotherapy after tumor removal in clinical settings.