Pang Guibin, Wei Siqi, Zhao Jian, Wang Fu-Jun
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China.
ECUST-FONOW Joint Research Center for Innovative Medicines, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China.
J Mater Chem B. 2023 Dec 13;11(48):11562-11577. doi: 10.1039/d3tb02118a.
To address the challenges posed by low immunogenicity and immune checkpoints during cancer treatment, we propose an alternative strategy that combines immunogenic cell death (ICD) effects with CD47/SIRPα blockade to reactivate phagocytosis of tumor cells by macrophages with polysaccharide-based drug delivery. In this study, the EGFR inhibitor gefitinib was identified as a novel CD47 modulator, which promoted the translocation of CD47 molecules from the cell membrane to endosomes through the EGFR-Rab5 pathway, leading to reduced cell surface CD47 levels and limiting interaction with SIRPα. Based on this finding, we developed prophagocytic mixed nanodrugs to enhance macrophage phagocytosis by encapsulating ICD inducer doxorubicin and CD47 inhibitor gefitinib with immunostimulatory polysaccharides from . This approach downregulated cell surface CD47 expression to attenuate "don't-eat-me" signaling, while increasing doxorubicin accumulation in tumors by inhibiting drug-resistance proteins, leading to more exposure of calreticulin and amplifying the "eat-me" signaling. experiments demonstrated that this approach significantly suppressed intraperitoneal tumor dissemination, reversed doxorubicin-induced weight loss, and effectively induced macrophage polarization, dendritic cell maturation, and CD8 T cell activation. These findings highlighted the significant potential of our macrophage-centered therapeutic strategy using polysaccharide-based nanocarriers and provided new perspectives for chemoimmunotherapy.
为应对癌症治疗过程中低免疫原性和免疫检查点带来的挑战，我们提出了一种替代策略，即将免疫原性细胞死亡（ICD）效应与CD47/SIRPα阻断相结合，通过基于多糖的药物递送重新激活巨噬细胞对肿瘤细胞的吞噬作用。在本研究中，表皮生长因子受体（EGFR）抑制剂吉非替尼被鉴定为一种新型的CD47调节剂，它通过EGFR-Rab5途径促进CD47分子从细胞膜向内体的转运，导致细胞表面CD47水平降低，并限制其与信号调节蛋白α（SIRPα）的相互作用。基于这一发现，我们开发了促吞噬混合纳米药物，通过将ICD诱导剂阿霉素和CD47抑制剂吉非替尼与来自[具体来源未提及]的免疫刺激多糖封装在一起，增强巨噬细胞的吞噬作用。这种方法下调细胞表面CD47的表达以减弱“别吃我”信号，同时通过抑制耐药蛋白增加阿霉素在肿瘤中的蓄积，导致钙网蛋白更多暴露并放大“吃我”信号。实验表明，这种方法显著抑制了腹腔肿瘤的扩散，逆转了阿霉素诱导的体重减轻，并有效诱导了巨噬细胞极化、树突状细胞成熟和CD8 + T细胞活化。这些发现突出了我们以巨噬细胞为中心、使用基于多糖的纳米载体的治疗策略的巨大潜力，并为化学免疫疗法提供了新的视角。
