Polyphenol-based pH-responsive nanoparticles enhance chemo-immunotherapy in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is challenging to treat due to its difficulty in early diagnosis, highly invasive nature, and high metastatic potential. Currently, the primary treatments for PDAC are chemotherapy and immunotherapy. However, the abundance of extracellular matrix and immunosuppressive cells in the tumor microenvironment (TME) severely impedes the effectiveness of chemotherapy and immunotherapy, promoting tumor growth and metastasis. Indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive tryptophan-metabolizing enzyme, is upregulated in PDAC and degrades tryptophan (Trp) into kynurenine (Kyn), which is toxic to effector T cells and induces regulatory T cells (Treg) recruitment. Herein, we propose a concise strategy to construct a biocompatible, polyphenol-based, pH-responsive nanoparticle to co-deliver docetaxel (DTX) and NLG919 (an IDO1 inhibitor) to significantly enhance chemo-immunotherapy for PDAC by remodeling the TME. The DTX/NLG919-loaded nanoparticles (FPND) effectively elicited immunogenic cell death (ICD) in PDAC cells while limiting immunosuppressive Kyn production through IDO1 inhibition. FPND triggered an effective anti-tumor immune response, characterized by increased CD8⁺ T cells infiltration and decreased Treg recruitment, leading to significant inhibition of subcutaneous tumor growth in KPC mice through a combination of chemotherapy and immunotherapy. Overall, FPND nanoparticles showed excellent anti-tumor efficacy as a PDAC therapeutic strategy with broad potential in precision medicine.