Exploiting Tumor Cell Invasiveness to Construct an Isolated Niche for Postoperative Immunotherapy

ABSTRACT Residual tumor cells persisting in the surgical bed are the principal drivers of postoperative tumor recurrence, yet the immunosuppressive wound healing microenvironment limits immune activation and compromises antigen enrichment and cross‐presentation. To address this issue, we exploited tumor cell invasiveness to construct isolated niches that confine the cells in micron‐scale chambers shielded from external microenvironmental perturbations. For proof of principle, we fabricated a hyaluronic acid‐based double‐network hydrogel comprising HAMA and PEGDA. Hyaluronidase‐dependent invasive tumor cells degrade the hydrogel to form isolated niches and are physically confined. The hydrogel releases DOX/LDH‐engineered Escherichia coli minicells that accumulate in niches, eradicating trapped tumor cells via high local DOX concentrations. Spatial confinement enriches tumor antigens and excludes normal tissue proteins, improving LDH‐mediated antigen capture. Minicells then deliver antigens to dendritic cells; post‐phagocytosis, LDH releases antigens, and Mn 2 + activates the cGAS‐STING pathway, synergistically boosting immune activation.