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

Area of Science:

• Oncology
• Nanotechnology
• Immunotherapy

Background:

• Pancreatic cancer (PC) has a poor prognosis due to its aggressive nature and limited therapeutic options.
• Activated pancreatic stellate cells (PSCs) and pancreatic cancer cells (PCCs) create a fibrotic barrier and immunosuppressive tumor microenvironment (TME), hindering treatment efficacy.
• A dual-targeting strategy is needed to simultaneously target PCCs and PSCs for improved PC treatment.

Purpose of the Study:

• To develop a peptide-based nanoparticle (DP-KPT-CG@PA) for co-delivery of KPT-6566 and a PD-L1-blocking peptide.
• To investigate the nanoparticle's ability to target PCCs and PSCs, revert activated PSCs (aPSCs) to quiescence, and suppress PCC proliferation.
• To evaluate the synergistic effect of the nanoparticle and PD-L1 blockade on enhancing pancreatic cancer immunotherapy.

Main Methods:

• Design and synthesis of two amphiphilic peptides: C16-LLGG-COO-^DPPA-1 (DPPA-1@PA) and DSPE-PEG-NHS-CGKRK (CGKRK@PA).
• Co-assembly of peptides to encapsulate KPT-6566, forming the peptide-based nanoparticle DP-KPT-CG@PA.
• Evaluation of the nanoparticle's targeting capabilities, therapeutic effects on PCCs and PSCs, and immune reprogramming in the tumor immune microenvironment (TIME).

Main Results:

• The DP-KPT-CG@PA nanoparticle effectively co-delivers KPT-6566 to target PCCs and PSCs.
• KPT-6566 reprograms the TIME, enhancing anti-PD-L1 immunotherapy efficacy.
• The nanoparticle suppresses PCC proliferation and induces PD-L1 expression, increasing sensitivity to PD-L1-targeted therapies.

Conclusions:

• The developed peptide-based nanoparticle offers a promising dual-targeting strategy for pancreatic cancer.
• Co-delivery of KPT-6566 and PD-L1 blockade via DP-KPT-CG@PA enhances anti-tumor efficacy and immunotherapy response.
• This approach holds potential for improving treatment outcomes in pancreatic cancer patients.