免疫检查点抑制剂（ICI）因其对三阴性乳腺癌（TNBC）的治疗效果而备受关注，然而ICI的应答率受到T细胞浸润不足的限制。因此，必须开发替代策略改善ICI对不应答TNBC病例的治疗效果。本研究评估了pH响应性纳米胶束（P/A/B@NM）共载帕妥珠单抗（PTX）、CXCR4拮抗剂AMD3100和PD-1/PD-L1抑制剂BMS-1激活T细胞介导的抗肿瘤免疫反应的疗效，以4T1抗PD-1耐药性乳腺肿瘤模型为研究对象。在体外，通过评估细胞存活率、迁移和侵袭来研究P/A/B@NM的pH响应性抗肿瘤效果。在体内，利用IVIS光谱成像仪可视化P/A/B@NM在4T1原位TNBC模型中的分布。评估共传递纳米载体的疗效通过监测小鼠生存率、肿瘤生长和转移、癌相关成纤维细胞（CAFs）介导的肿瘤结构和免疫抑制微环境成分，以及CD8+T细胞的招募和浸润。制备的P/A/B@NM在酸性微环境中对MDA-MB-231细胞表现出显著的细胞毒性，IC50为105 μg/mL。此外，它能够显著抑制肿瘤细胞的迁移和侵袭。基于共传递纳米载体的P/A/B@NM在肿瘤部位高效积累并以pH响应性的方式释放药物。纳米药物PTX、AMD3100和BMS-1组合方案通过抑制CXCL12/CXCR4轴块age部肿瘤生长和肺/肝转移，并通过诱导免疫细胞死亡重编程肿瘤结构和免疫抑制微环境，诱导抗肿瘤免疫反应。因此，触发CD8+ T细胞浸润到肿瘤部位，从而协同增强ICI治疗的疗效。这些结果表明，利用P/A/B@NM的联合治疗能够重塑CAFs介导的肿瘤结构和免疫抑制微环境，提高CD8+ T细胞的浸润，从而重新激活对不应答TNBC病例的抗肿瘤免疫。

© 2023张等

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/B@NM) 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.In vitro, pH-responsive antitumor effect of P/A/B@NM was investigated by assessing cell viability, migration and invasion. In vivo, the distribution of P/A/B@NM 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.The prepared P/A/B@NM in acid microenvironment demonstrates remarkable cytotoxicity against MDA-MB-231 cells, with an IC50 of 105 μg/mL. Additionally, it exhibits substantial inhibition of tumor cell migration and invasion. The P/A/B@NM based on co-delivery nanocarriers efficiently accumulate at the tumor site and release the drugs in a pH-responsive controlled manner. The nanomedicine-PTX, AMD3100, and BMS-1 formulation significantly inhibits tumor growth and lung/liver metastasis by inducing antitumor immune responses via CXCL12/CXCR4 axis blockade, and immunogenic cell death to reprogramme both tumor stroma and immunosuppressive microenvironment. As a result, CD8+ T cell infiltration is triggered into the tumor site, boosting the efficacy of ICI therapy synergistically.These results demonstrate that combination therapy using P/A/B@NM reshapes CAFs-mediated tumor stroma and immunosuppressive microenvironment, which can enhance the infiltration of CD8+ T cells, thereby reactivating anti-tumor immunity for non-responsive TNBC cases.© 2023 Zhang et al.