Localized Delivery of Anti-CD40/PD-1 Immunotherapy via a Polymeric Implant is Efficacious, Remodels the Tumor Immune Microenvironment and Improves Safety in a PDAC Mouse Model.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive to immune checkpoint blockade due to its immunosuppressive tumor microenvironment and the systemic toxicity associated with combination immunotherapies. Here, this work reports the development of a biodegradable implant, designed for the localized co-delivery of CD40 agonist and anti-PD-1 antibodies, and evaluate its therapeutic effect in an aggressive KPC mouse model of PDAC. This localized approach significantly reduces tumor burden compared to controls and markedly attenuated systemic toxicities relative to conventional systemic administration. Immune profiling via transcriptomic analysis and flow cytometry revealed tumor microenvironment reprogramming, characterized by elevated dendritic cell activation (CD86⁺CD11c⁺), increased CD8⁺ T cell infiltration, and reduced expression of genes associated with myeloid-derived suppressor cells. Histopathology confirms improved tolerability. These findings demonstrate that localized co-delivery of CD40 and PD-1 immunotherapy via a biodegradable implant promotes anti-tumor immunity while reducing systemic toxicity and immunotherapy-associated complications. This strategy offers a promising alternative to systemic immunotherapy for PDAC and may help overcome the barriers of toxicity and immune resistance in this disease.