Interferon-γ (IFN-γ) is a key mediator in antitumor immunity and immunotherapy responses, yet its clinical applications remain restricted to chronic granulomatous disease and malignant osteopetrosis. IFN-γ 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-γ with Toll-like receptor (TLR) agonists that holds significant promise for cancer treatment. Previously, we demonstrated chitosan (Ch)/poly(γ-glutamic acid) (γ-PGA) nanoparticles (NPs), known to activate TLRs, as adjuvants to radiotherapy by remodeling breast tumor microenvironment and systemic immunosuppression. These immunomodulatory abilities make Ch/γ-PGA NPs promising adjuvants to IFN-γ-based therapies. Here, we addressed the synergistic therapeutic potential of combining Ch/γ-PGA NPs with IFN-γ 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-γ 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-γ 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-of-concept study suggests that Ch/γ-PGA NPs potentiate IFN-γ effects to reduce tumor progression, presenting a novel approach for anticancer strategies.