Chitosan/γ-PGA nanoparticles and IFN-γ immunotherapy: A dual approach for triple-negative breast cancer treatment

• DOI: 10.1016/j.jconrel.2025.01.042
• Publication Date: 2025-01-24T09:23:40Z
• Authors: Flávia Castro; Marta Laranjeiro ...; Catarina Leite Pe...; Karine Serre; Ângela Margarida ...; Bruno Cavadas; Mário Adolfo Barbosa; Karim Vermaelen; Sergio León; Diego Serrano; Fátima Gärtner; Alfonso Calvo; Raquel Madeira Go...; Olivier De Wever; Maria José Oliveira
• Keywords: Immunosuppression

Interferon-gamma (IFN-gamma) is a key mediator in antitumor immunity and immunotherapy responses, yet its clinical applications remain restricted to chronic granulomatous disease and malignant osteopetrosis. IFN-gamma effectiveness as a standalone treatment has shown limited success in clinical trials and its potential for synergistic effects when combined with immunotherapies is under clinical exploration. A particularly compelling combination is that of IFN-gamma with Toll-like receptor (TLR) agonists that holds significant promise for cancer treatment. Previously, we demonstrated chitosan (Ch)/poly(gamma-glutamic acid) (gamma-PGA) nanoparticles (NPs), known to activate TLRs, as adjuvants to radiotherapy by remodeling breast tumor microenvironment and systemic immunosuppression. These immunomodulatory abilities make Ch/gamma-PGA NPs promising adjuvants to IFN-gamma-based therapies. Here, we addressed the synergistic therapeutic potential of combining Ch/gamma-PGA NPs with IFN-gamma therapy in the 4T1 orthotopic breast tumor mouse model. While control animals (placebo-treated) had progressive tumor growth and lung metastases, those treated with either NPs or IFN-gamma alone had a significant slower tumor growth. Remarkably, primary tumor growth was halted throughout the duration of the treatment when both treatments were combined. Although the animals did not achieve durable complete responses upon treatment withdrawal, it was notable that the NPs plus IFN-gamma group presented a lower lung metastatic burden compared to other groups. Systemically, the combination therapy slightly attenuated immunosuppression and the percentage of splenic myeloid cells, while increased the percentage of T helper 1 cells and of cytotoxic T cells. Overall, this proof-ofconcept study suggests that Ch/gamma-PGA NPs potentiate IFN-gamma effects to reduce tumor progression, presenting a novel approach for anticancer strategies.