4.8 Article

Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases

Journal

BIOACTIVE MATERIALS
Volume 27, Issue -, Pages 474-487

Publisher

KEAI PUBLISHING LTD
DOI: 10.1016/j.bioactmat.2023.04.021

Keywords

Breast cancer brain metastases; Drug delivery; Immunogenic cell death; Microenvironmental regulation; STAT3

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The poor outcomes of triple-negative breast cancer brain metastases are due to the lack of effective therapies. Immunotherapy has limitations for TNBC brain metastases due to non-immunogenicity of tumors and strong immunosuppressive environment. This study proposed a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and developed reduction-sensitive immune microenvironment regulation nano-materials (SIL@T). SIL@T showed dual immunomodulatory functions and provided a promising immune synergistic therapy strategy for breast cancer brain metastases.
A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases. Immunotherapy has made progress in the treatment of tumors, but limited by the non-immunogenicity of tumors and strong immunosuppressive environment, patients with TNBC brain metastases have not yet benefited from immunotherapy. Dual immunoregulatory strategies with enhanced immune acti-vation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients. Here, we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nano-materials (SIL@T). SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells, releasing silybin and oxaliplatin responsively in the cells. SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals. Mecha-nistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells, activate immune responses and increase infiltration of CD8+ T cells. Meanwhile, the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed. This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

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