Immunosuppressive microenvironment improvement and treatment of aggressive malignancy pancreatic ductal adenocarcinoma based on local administration of injectable hydrogel

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is among the most devastating solid malignancies globally owing to the lack of effective therapies, which is characterized by a profuse fibrotic stromal reaction, hypoxia, and an immunosuppressive microenvironment. Although immunotherapy shows tremendous clinical benefits for the management of solid tumors, to date, immunotherapy has largely failed to produce significant improvements in PDAC survival. Thus, the strategy that specifically targets the complicated immunosuppressive tumor microenvironment (TME) and immune-related therapeutic resistance in PDAC is an urgent need. Photothermal immunotherapy, which combines "local tumor hyperthermia" with "immune remodeling", is an effective modality for PDAC treatment. This study develops an injectable peptide-based hydrogel for integration with near-infrared photothermal pigment (biliverdin, (BV)) and a clinically approved immunomodulatory peptide (thymopentin, (TP5)) for local PDAC administration and treatment. The tumors are efficiently ablated using local photothermal therapy. Moreover, the immune response in vivo is correspondingly activated to transform "cold" TME into "hot" TME by improving T-cell infiltration and alleviating tumor hypoxia, thus effectively inhibiting tumor recurrence and metastasis. The strategy developed in this study provides a potent method for the treatment of relapsed and refractory pancreatic malignancies with a poor immune response.