化学免疫疗法已被批准作为三阴性乳腺癌（TNBC）的标准治疗方法，但临床结果仍不令人满意。异常的表观遗传调控与获得性耐药和 T 细胞耗竭有关，这是 TNBC 对化学免疫治疗反应不佳的关键因素。在此，制备了共载紫杉醇（PTX）和地西他滨（DAC）的巨噬细胞伪装纳米诱导剂（P/D-mMSNs），与PD-1阻断疗法相结合，希望通过肿瘤组织的去甲基化来提高化学免疫疗法的疗效。巨噬细胞囊泡的伪装赋予 P/D-mMSN 肿瘤归巢特性。首先，DAC可以实现肿瘤组织的去甲基化，增强肿瘤细胞对PTX的敏感性。随后，PTX诱导肿瘤细胞免疫原性死亡，促进树突状细胞吞噬死亡细胞，并招募细胞毒性T细胞浸润肿瘤。最后，DAC 可逆转 T 细胞耗竭并促进免疫检查点阻断疗法。 P/D-mMSNs 可能是未来药物递送设计和 TNBC 癌症联合治疗的有希望的候选者。© 2023 中国药学会和中国医学科学院药物研究所。由 Elsevier B.V. 制作和主持

Chemoimmunotherapy has been approved as standard treatment for triple-negative breast cancer (TNBC), but the clinical outcomes remain unsatisfied. Abnormal epigenetic regulation is associated with acquired drug resistance and T cell exhaustion, which is a critical factor for the poor response to chemoimmunotherapy in TNBC. Herein, macrophage-camouflaged nanoinducers co-loaded with paclitaxel (PTX) and decitabine (DAC) (P/D-mMSNs) were prepared in combination with PD-1 blockade therapy, hoping to improve the efficacy of chemoimmunotherapy through the demethylation of tumor tissue. Camouflage of macrophage vesicle confers P/D-mMSNs with tumor-homing properties. First, DAC can achieve demethylation of tumor tissue and enhance the sensitivity of tumor cells to PTX. Subsequently, PTX induces immunogenic death of tumor cells, promotes phagocytosis of dead cells by dendritic cells, and recruits cytotoxic T cells to infiltrate tumors. Finally, DAC reverses T cell depletion and facilitates immune checkpoint blockade therapy. P/D-mMSNs may be a promising candidate for future drug delivery design and cancer combination therapy in TNBC.© 2023 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.