Background and Purpose: Inflammation associated with the tumour microenvironment (TME) plays a critical role in the cancer development, and immunotherapeutic strategies that aim to modulate the immune response in cancer have been crucial. In this study, a Methotrexate-loaded (MTX) poly(lactic-co-glycolic acid)-based (PLGA) drug nanocarrier covered with polyethyleneimine (Pei) and hyaluronic acid (HA) was developed and combined with anti-PD-L1 immune checkpoint inhibitor to investigate the anti-cancer and immunomodulatory performance in the breast cancer TME. Experimental Approach: From the allographic model of orthotopic tumour growth, the tumours were evaluated by qRT-PCR and immunohistochemistry. Complementary analysis of cell death profile, cell migration and macrophage polarization were evaluated in vitro. Key Results: Naked or HA-coated PeiPLGA-MTX nanoparticles (NPs) used alone or combined with anti-PD-L1 promoted tumorigenic course modification as well as TME immunomodulation with significant reduction of primary tumour and metastasis. For the first time, we reported the involvement of M2 macrophages as major orchestrator of this response via NPs-mediated IL-10/STAT3/NF-κB downregulation. The suppression of this signalling axis seems to have disrupted the crosstalk between immune and malignant cells, reducing critical pro-tumour events such as: immune escape; cell survival; drug and apoptosis resistance, as well as some key mechanisms in the epithelial-mesenchymal transition. Conclusion and Implications: These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of an effective This article is protected by copyright. All rights reserved. and promising drug nanocarrier capable of satisfactorily immunomodulating the TME and providing a favourable outcome in breast cancer.

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