A thermosensitive hydrogel with synergistic stromal targeting and antitumor immunity modulation for pancreatic cancer immunotherapy

Pancreatic cancer is intrinsically characterized by an immunosuppressive microenvironment, in which the malignant extracellular matrix (ECM) creates a barrier that significantly impedes drug delivery, thereby undermining the overall anti-tumor immune responses. In this study, we present a novel thermosensitive hydrogel (SCC15+PLHCu@Gel) that co-deliver two types of nanoparticles loaded with the disulfiram derivative CPD12C15 (SCC15) and tumor-targeting Cu²⁺ (PLHCu) to overcome the degradation of CPD12C15 induced by Cu²⁺ within the same nano formulation. SCC15 effectively reduced α-SMA and Collagen I and increased lipid droplets in the cancer-associated fibroblasts (CAFs) by inhibiting the Smad3 pathway, which was consistent with the ECM depletion achieved by using the <i>in-vivo</i> dosing of SCC15+PLHCu@Gel. In addition, the <i>in-vivo</i> treatment of SCC15+PLHCu@Gel significantly elevated pro-inflammatory cytokines IFN-γ, TNF-α and IL-12, indicating the remodeling of the suppressive tumor microenvironment. Finally, the immunity modulation effects of SCC15+PLHCu@Gel were evaluated on the enhancement of tumor-infiltrating cytotoxic CD8⁺ T cells, maturation of dendritic cells as well as inhibition of immunosuppressive Tregs and MDSCs. These enhanced antitumor immunity responses might be related to the immunogenic cell death (ICD) effects. Thereby, this study presents a promising therapeutic strategy for targeting the ECM and enhancing the immune responses against pancreatic cancer.