Immunomodulatory Hydrogel Coupling Pyroptosis Amplification With T-Cell Modulation to Block Postoperative Tumor...

Postoperative tumor recurrence remains a fundamental limitation of curative cancer surgery, driven by residual malignant cells and a profoundly immunosuppressive postoperative microenvironment. Here, we report a tumor microenvironment-responsive hydrogel that couples self-amplifying pyroptosis with CD8⁺ T cells modulation to prevent postoperative tumor relapse. This hydrogel consists of a butyrate prodrug hydrogel and engineered bacterial membrane vesicles encoding a self-triggered gasdermin D-mediated pyroptosis program. Upon in situ gelation within the surgical cavity, the hydrogel undergoes controlled degradation to release the engineered pyroptosis-inducing vesicles and butyrate. The released membrane vesicles elevate intracellular gasdermin D levels while simultaneously activating the NLRP3-caspase-1 pathway, thereby triggering robust and self-amplifying pyroptosis in residual tumor cells. This lytic cell death eliminates residual malignancies and releases damage-associated molecular patterns that convert the postoperative niche from immunosuppressive to immunogenic and promote cytotoxic T lymphocytes recruitment. Concurrently, butyrate released from the hydrogel reprograms infiltrating CD8⁺ T cells, enhancing their effector function. By integrating tumor cell-intrinsic pyroptosis induction with modulation of antitumor CD8⁺ T cells, this combinatorial platform remodels the postoperative tumor microenvironment and provides durable protection against tumor regrowth. This work establishes a localized immunomodulatory strategy that directly addresses the long-standing challenge of postoperative tumor recurrence.