肿瘤微环境内，肿瘤细胞和免疫抑制性免疫细胞（包括髓源性抑制细胞(MDSCs)、肿瘤相关巨噬细胞(TAMs)和调节性T细胞）作为网络的节点构成了一个复杂的免疫抑制网络，彼此之间存在相互促进的关系，对自然杀伤(NK)细胞和细胞毒性T细胞有叠加抑制作用。打破这个网络的整体平衡对于肿瘤免疫疗法至关重要，因为对单个节点的调节可能会被网络中的其他因素稀释。为了在三阴性乳腺癌中实现多方面调节抗肿瘤免疫力，在这项研究中，通过pH敏感的两亲性聚（β-氨基酯）衍生物构建了一种称为BEM的微胶束，同时给予髓源性抑制剂entinostat (ENT)和免疫检查点抑制剂BMS-1。然后，BEM和清道夫受体A (SR-A) 配体硫酸葡聚糖（DXS）形成带有负电荷的纳米颗粒（BEN）。DXS在弱酸性肿瘤微环境中与BEN解离，并阻断TAMs上的SR-A，使其重新编程为M1型。带有正电荷的BEM通过增强肿瘤内渗透和细胞摄取在溶酶体中分离，随之ENT和BMS-1释放出来应用于MDSCs抑制和PD-1/PD-ligand 1通路阻断。因此，肿瘤中的NK细胞和CD8+T细胞增加，其效应因子也增加。激活的先天性和适应性抗肿瘤免疫应答抑制了肿瘤的生长和转移，并延长了携带4T1肿瘤的小鼠的生存时间。BEN通过多节点调节，为改善癌症免疫疗法提供了一种可靠的途径，通过摧毁肿瘤中的免疫抑制网络。

Inside the tumor microenvironment, a complicated immunosuppressive network is constituted by tumor cells and suppressive immune cells as its nodes, including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T cells, which have mutual promotion on each other and superimposed inhibition on natural killer (NK) cells and cytotoxic T cells. Breaking the whole balance of this web is critical to tumor immunotherapy since modulation on a single node may be diluted by other factors in the network. To achieve multifaceted regulation on antitumor immunity against triple-negative breast cancer, in this work, a micelle, termed BEM, co-delivering the MDSC inhibitor, entinostat (ENT), and the immune checkpoint inhibitor, BMS-1, was constructed with pH-sensitive amphiphilic poly(β-amino ester) derivatives. Then, BEM and the scavenger receptor A (SR-A) ligand dextran sulfate (DXS) formed a negatively charged nanoparticle (BEN). DXS detached from BEN in the weakly acidic tumor microenvironment and blocked SR-A on TAMs, reprogramming TAMs toward the M1 type. The positively charged BEM with facilitated intratumoral penetration and cellular uptake dissociated in the lysosomes, accompanied by the release of ENT and BMS-1 to suppress MDSCs and block the programmed cell death protein (PD)-1/PD-ligand 1 pathway, respectively. As a result, NK cells and CD8+ T cells in tumors were increased, as were their effector cytokines. The activated innate and adaptive antitumor immune responses suppressed the growth and metastasis of tumors and prolonged survival of 4T1 tumor-bearing mice. BEN provides a reliable approach for improving cancer immunotherapy by destroying the immunosuppression web in tumors via multinode regulation.