Targeting PIN1 in Pancreatic Tumor Microenvironment with Peptide Amphiphiles Unleashes Immune Checkpoint Therapy.

Pancreatic cancer (PC) is a highly aggressive malignancy with a dismal 5-year survival rate of only 12%. Currently, no effective therapeutic strategies can improve the prognosis of pancreatic cancer. The activation of quiescent pancreatic stellate cells (PSCs) and their crosstalk with pancreatic cancer cells (PCCs) lead to the formation of a fibrotic physical barrier and an immunosuppressive tumor microenvironment (TME), which severely impede drug delivery and penetration. To improve PC treatment, a dual-targeting strategy capable of simultaneously acting on PCCs and PSCs is urgently needed to revert activated PSCs (aPSCs) to their quiescent state and suppress the proliferation of PCCs. KPT-6566, a small-molecule inhibitor, shifts PSCs from an activated to a quiescent state, reprograms the tumor immune microenvironment (TIME) to enhance anti-PD-L1 immunotherapy efficacy, suppresses PCCs proliferation, and induces PD-L1 expression on PCC surfaces, thereby increasing sensitivity to PD-L1-targeted therapies. This study designs two amphiphilic peptides, C16-LLGG-COO-^DPPA-1(DPPA-1@PA) and DSPE-PEG-NHS-CGKRK(CGKRK@PA), which can co-assemble to encapsulate KPT-6566 and finally form a peptide-based nanoparticle termed DP-KPT-CG@PA. This nanoparticle precisely targets PCCs and PSCs to co-deliver KPT-6566, while synergizing with a PD-L1-blocking peptide to initiate immune checkpoint blockade therapy, thereby enhancing response rates to pancreatic cancer immunotherapy.