化疗可以诱导肿瘤细胞的免疫原性细胞死亡（ICD），为癌症治疗提供了新的可能性。然而，由于肿瘤微环境（TME）的抑制性质，产生的免疫反应的效率不足。在这里，我们开发了一种 pH/活性氧 (ROS) 双重响应系统来增强黑色素瘤的化学免疫治疗。该系统通过苯基硼酸（PBA）与唾液酸（SA）的特异性结合在肿瘤中有效积累。在肿瘤微环境（TME）的刺激下，纳米颗粒（NP）迅速膨胀并释放槲皮素（QUE）和阿霉素（DOX）。体外和体内结果一致表明，纳米粒子提高了抗肿瘤功效并延长了小鼠的生存期，显着增强了联合用药的效果。我们的研究表明 DOX 是一种 ICD 诱导剂，可刺激免疫反应并促进树突状细胞 (DC) 的成熟。此外，QUE 通过抑制环氧合酶 2 (COX2)-前列腺素 E2 (PGE2) 轴充当 TME 调节剂，影响多种免疫细胞，包括增加细胞毒性 T 细胞 (CLT) 浸润、促进 M1 巨噬细胞极化和减少调节性 T细胞（Treg）浸润。该组合通过重塑免疫抑制微环境，协同促进化学免疫疗法的疗效。这项工作提出了一种提高化疗药物抗肿瘤效率的有前景的策略。© 2024 作者。

Chemotherapeutics can induce immunogenic cell death (ICD) in tumor cells, offering new possibilities for cancer therapy. However, the efficiency of the immune response generated is insufficient due to the inhibitory nature of the tumor microenvironment (TME). Here, we developed a pH/reactive oxygen species (ROS) dual-response system to enhance chemoimmunotherapy for melanoma. The system productively accumulated in tumors by specific binding of phenylboronic acid (PBA) to sialic acids (SA). The nanoparticles (NPs) rapidly swelled and released quercetin (QUE) and doxorubicin (DOX) upon the stimulation of tumor microenvironment (TME). The in vitro and in vivo results consistently demonstrated that the NPs improved anti-tumor efficacy and prolonged survival of mice, significantly enhancing the effects of the combination. Our study revealed DOX was an ICD inducer, stimulating immune responses and promoting maturation of dendritic cells (DCs). Additionally, QUE served as a TME regulator by inhibiting the cyclooxygenase-2 (COX2)-prostaglandin E2 (PGE2) axis, which influenced various immune cells, including increasing cytotoxic T cells (CLTs) infiltration, promoting M1 macrophage polarization, and reducing regulatory T cells (Tregs) infiltration. The combination synergistically facilitated chemoimmunotherapy efficacy by remodeling the immunosuppressive microenvironment. This work presents a promising strategy to increase anti-tumor efficiency of chemotherapeutic agents.© 2024 The Authors.