Photodynamic Priming and Minocycline Overcome Chemoresistance by Reprogramming the Pancreatic Tumor Immune...

Area of Science:

• Oncology
• Nanomedicine
• Immunotherapy

Background:

• Pancreatic ductal adenocarcinoma (PDAC) exhibits significant drug resistance due to its dense stroma, DNA repair mechanisms, drug efflux, and immunosuppressive tumor microenvironment (TME).
• Overcoming these resistance factors is crucial for developing effective PDAC therapies.

Purpose of the Study:

• To develop a photoactivatable multi-inhibitor liposome (PMIL) platform for enhanced pancreatic cancer treatment.
• To leverage FDA-approved agents for synergistic effects, including immunomodulation and overcoming drug resistance.

Main Methods:

• Utilized PMILs encapsulating minocycline and irinotecan (IRI), with a benzoporphyrin derivative for photodynamic priming (PDP).
• Investigated light-triggered PDP followed by IRI release in an orthotopic PDAC mouse model.
• Assessed drug accumulation, resistance marker downregulation, immune cell infiltration, and tumor regression.

Main Results:

• PMILs demonstrated light-triggered PDP and enhanced intratumoral IRI accumulation.
• Dual priming downregulated key IRI resistance mediators (Tdp1 and ABCG2).
• Observed significant immune activation, including increased CD8+ T cells and reduced regulatory T cells/M2 macrophages, leading to tumor regression and improved survival (63%).

Conclusions:

• The PMIL platform effectively reprograms the TME and enhances antitumor immunity in PDAC.
• This approach offers a clinically translatable strategy to overcome drug resistance and sensitize PDAC to chemo- and immunotherapy.