Phagocyte-mediated programmed cell removal (PrCR) plays an important role in the immunosurveillance and elimination of cancer cells. The induction of PrCR is elevated by exposed calreticulin (CRT) on cell surface as a “eat me” signal, and countered by "don't eat me" signal, CD47. Thus, well-tolerated CRT exposure inducers are benefit for the outcome of anti-CD47 therapy. Herein, fullerenol nanoparticle (fNP) with special surface property is found to trigger CRT exposure in 7 out of 12 human cancer cell lines by inducing basal ER stress without the occurrence of immunogenic cell death. Increased CRT exposure by fNP elicits efficient PrCR, which is further enhanced by the combination of fNP and anti-CD47 mAb in vivo. Moreover, the combined therapy shows significantly increased anti-tumor efficiency compared with anti-CD47 mAb alone in both U87MG subcutaneous glioblastoma model and 143B orthotopic osteosarcoma model. Even in combination with half dose of anti-CD47 mAbs shows a similar anti-tumor efficiency with full-dose anti-CD47 mAbs alone, suggesting the role of fNP in reducing the amount of anti-CD47 mAbs. Moreover, the combination treatment promotes M2-to-M1 repolarization of macrophage within the tumor microenvironment. These findings validate our strategy as an effective platform for combining fNP with anti-CD47 therapy.

吞噬细胞介导的程序性细胞去除（PrCR）在免疫监视和消除癌细胞中起重要作用。PrCR的诱导通过细胞表面暴露的钙网蛋白（CRT）作为“吞噬我”信号而升高，并被“不吞噬我”信号CD47抵消。因此，耐受性良好的CRT暴露诱导剂有益于抗CD47治疗的结果。在本文中，发现具有特殊表面特性的富勒烯醇纳米颗粒（fNP）通过诱导基础ER应激而在未发生免疫原性细胞死亡的情况下，触发12个人类癌细胞中的7种引起CRT暴露。fNP增加的CRT暴露会引起有效的PrCR，fNP和抗CD47 mAb在体内的结合会进一步增强PrCR。此外，在U87MG皮下成胶质细胞瘤模型和143B原位骨肉瘤模型中，与单独使用抗CD47 mAb相比，联合治疗显示出显着提高的抗肿瘤效率。即使与半剂量的抗CD47 mAb组合使用，也显示出与单独的全剂量抗CD47 mAb相似的抗肿瘤效率，这表明fNP在减少抗CD47 mAb数量中的作用。此外，联合治疗促进了肿瘤微环境中巨噬细胞的M2至M1重极化。这些发现证实了我们的策略是将fNP与抗CD47治疗相结合的有效平台。提示fNP在减少抗CD47 mAb数量中的作用。此外，联合治疗促进了肿瘤微环境中巨噬细胞的M2至M1重极化。这些发现证实了我们的策略是将fNP与抗CD47治疗相结合的有效平台。提示fNP在减少抗CD47 mAb数量中的作用。此外，联合治疗促进了肿瘤微环境中巨噬细胞的M2至M1重极化。这些发现证实了我们的策略是将fNP与抗CD47治疗相结合的有效平台。