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

Abstract Injectable scaffold delivery is a strategy to enhance the efficacy of cancer vaccine immunotherapy. The choice of scaffold biomaterial is crucial, impacting both vaccine release kinetics and immune stimulation via the host response. Extracellular matrix (ECM) scaffolds prepared from decellularized tissues facilitate a pro‐healing inflammatory response that promotes local cancer immune surveillance. Here, an ECM scaffold‐assisted therapeutic cancer vaccine that maintains an immune microenvironment consistent with tissue reconstruction is engineered. Several immune‐stimulating adjuvants are screened to develop a cancer vaccine formulated with decellularized small intestinal submucosa (SIS) ECM scaffold co‐delivery. It is found that the STING pathway agonist cyclic di‐AMP most effectively induces cytotoxic immunity in an ECM scaffold vaccine, without compromising key interleukin 4 (IL‐4) mediated immune pathways associated with healing. ECM scaffold delivery enhances therapeutic vaccine efficacy, curing 50–75% of established E.G‐7OVA lymphoma tumors in mice, while none are cured with soluble vaccine. SIS‐ECM scaffold‐assisted vaccination prolonged antigen exposure is dependent on CD8 ⁺ cytotoxic T cells and generates long‐term antigen‐specific immune memory for at least 10 months post‐vaccination. This study shows that an ECM scaffold is a promising delivery vehicle to enhance cancer vaccine efficacy while being orthogonal to characteristics of pro‐healing immune hallmarks.