Co-Delivery Nanomicelles for Potentiating TNBC Immunotherapy by Synergetically Reshaping CAFs-Mediated Tumor Stroma and Reprogramming Immunosuppressive Microenvironment

作者：Yue Zhang, Xue Han, Ke Wang, Da Liu, Xiaoyun Ding, Zhiqiang Hu, Jing Wang · 发表于：International Journal of Nanomedicine · 年份：2023 · DOI：10.2147/ijn.s418100 · 被引用次数：41 · 研究领域：Nanoplatforms for cancer theranostics、Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses

Purpose: Immune checkpoint inhibitors (ICI) have received the most attention for triple negative breast cancer (TNBC), while the response rate to ICI remains limited due to insufficient T cell infiltration. It is therefore essential that alternative strategies are developed to improve the therapeutic outcomes of ICI in non-responsive TNBC cases. The efficacy of pH-responsive nanomicelles (P/A/ [email protected] ) co-loaded with paclitaxel (PTX), CXCR4 antagonist AMD3100, and PD-1/PD-L1 inhibitor BMS-1 activating the T cell-mediated antitumor immune response were evaluated using a 4T1 antiPD-1-resistance breast tumor model. Methods: In vitro, pH-responsive antitumor effect of P/A/ [email protected] was investigated by assessing cell viability, migration and invasion. In vivo, the distribution of P/A/ [email protected] was visualized in 4T1 orthotopic TNBC model using an IVIS spectrum imaging instrument. The efficacy of the co-delivery nanocarriers was evaluated by monitoring mouse survival, tumor growth and metastasis, cancer-associated fibroblasts (CAFs)-mediated tumor stroma and immunosuppressive microenvironment components, and the recruitment and infiltration of CD8 + T cells. Results: The prepared P/A/ [email protected] in acid microenvironment demonstrates remarkable cytotoxicity against MDA-MB-231 cells, with an IC 50 of 105 μg/mL. Additionally, it exhibits substantial inhibition of tumor cell migration and invasion. The P/A/ [email protected] based on co-delivery nanoc...