Immunomodulator-Mediated Suppressive Tumor Immune Microenvironment Remodeling Nanoplatform for Enhanced Immuno/Chemo/Photothermal Combination Therapy of Triple Negative Breast Cancer.

ABSTRACT

Despite immunotherapy having revolutionized cancer therapy, the efficacy of immunotherapy in triple-negative breast cancer (TNBC) is seriously restricted due to the insufficient infiltration of mature dendritic cells (DCs) and the highly diffusion of immunosuppressive cells in the tumor microenvironment. Herein, an immunomodulatory nanoplatform (HA/Lipo@MTO@IMQ), in which the DCs could be maximally activated, was engineered to remarkably eradicate the tumor via the combination of suppressive tumor immune microenvironment reversal immunotherapy, chemotherapy, and photothermal therapy. It was noticed that the immunotherapy efficacy could be significantly facilitated by this triple-assistance therapy First, a robust immunogenic cell death (ICD) effect was induced by mitoxantrone hydrochloride (MTO) to boost DCs maturation and cytotoxic T lymphocytes infiltration. Second, the powerful promaturation property of the toll-like receptor 7/8 (TLR7/8) agonist on DCs simultaneously strengthened the ICD effect and restricted antitumor immunity to the tumor bed and lymph nodes. On this basis, tumor-associated macrophages were also dramatically repolarized toward the antitumor M1 phenotype in response to TLR7/8 agonist to intensify the phagocytosis and reverse the immunosuppressive microenvironment. Furthermore, the recruitment of immunocompetent cells and tumor growth inhibition were further promoted by the photothermal characteristic. The nanoplatform with no conspicuous untoward effects exhibited a splendid ability to activate the systemic immune system so as to increase the immunogenicity of the tumor microenvironment, thus enhancing the tumor killing effect. Taken together, HA/Lipo@MTO@IMQ might highlight an efficient combination of therapeutic modality for TNBC.