Cold Atmospheric Plasma‐Activated Decellularized Extracellular Matrix Gel as a Tumor‐Infiltrating Immunoactivation Platform for Post‐Surgical Cancer Immunotherapy

Abstract

ABSTRACT Surgical resection is a frontline treatment for many solid tumors; however, residual tumor cells in the surgical cavity often lead to recurrence and metastasis. Adjuvant therapies are used to mitigate this risk but are frequently limited by systemic toxicity and variable efficacy. Here, we present an injectable, cold atmospheric plasma (CAP)‐loaded decellularized tumor extracellular matrix (DECM) hydrogel (denoted as CAP‐DECM gel) as a novel in situ tumor‐infiltrating immunoactivation platform for post‐surgical cancer immunotherapy. These gels combine two critical functionalities: the attraction of residual tumor cells by DECM‐derived chemokines and cytokines, and the local induction of immunogenic cell death (ICD) through CAP‐derived reactive species. Studies demonstrate that CAP‐DECM gels effectively recruit tumor cells, promote ICD hallmarks, activate various immune cells, including dendritic cells and macrophages, and elicit robust T‐cell responses. In murine post‐resection melanoma and breast cancer models, CAP‐DECM gels significantly suppressed tumor recurrence, reprogrammed the tumor microenvironment toward an immune‐supportive phenotype, and triggered systemic anti‐tumor immunity. Furthermore, combining CAP‐DECM gels with anti‐PD‐L1 checkpoint blockade therapy enhanced long‐term survival and conferred resistance to tumor rechallenge. Our results suggest that this tumor‐infiltrating immunoactivation platform transforms the surgical cavity into a self‐contained immune activation depot and offers a promising, personalized strategy for preventing tumor relapse.