SIRPα-TRAIL融合蛋白通过靶向免疫检查点及细胞内途径促进卵巢癌死亡的研究

肿瘤免疫治疗旨在激活人体免疫系统，依靠自身免疫机能攻击肿瘤细胞死亡，CD47-SIRPα作为免疫检查点，靶向阻断其“别吃我”信号的肿瘤治疗备受关注。然而，当以免疫检查点疗法为主流开始治疗癌症时，卵巢癌这类“冷肿瘤”却出现了低应答等局限性，如何转“冷”为“热”提高免疫治疗的效果亟待解决。团队前期研究证实凋亡/自噬等细胞内途径的变化可调控卵巢癌发生发展及耐药。据此推测，免疫检查点抑制联合细胞内途径的双重抗肿瘤作用可能是解决问题的关键。本课题拟制备SIRPα-TRAIL融合蛋白，阻断“不吃我”信号，抑制肿瘤细胞免疫逃逸，恢复巨噬细胞对肿瘤细胞的吞噬作用；同时触发的细胞死亡可招募巨噬细胞吞噬肿瘤细胞，发挥双重抗癌作用。从分子、细胞、组织、动物模型等多层次，探究融合蛋白作用效果和机制。这既解决了单一治疗活性低、不良反应等弊端，又发挥了双重抗肿瘤作用，扩大了药物治疗效果，为卵巢癌临床治疗提供了新思路。

Tumor immunotherapy aims to activate the human immune system and attack tumor cell death by relying on autoimmune function. As an immune checkpoint, tumor therapy targeting CD47-SIRPα to block its "don't eat me" signal has attracted much attention. However, when immune checkpoint therapy is the essential aspect in the treatment of cancer, there are some limitations such as low response to "cold tumor" such as ovarian cancer. It is urgent to solve how to change "cold" to "hot" to improve the effect of immunotherapy. Previous team studies have confirmed that changes in intracellular pathways such as apoptosis/autophagy can regulate the occurrence, development and drug resistance of ovarian cancer. It is speculated that the dual anti-tumor effect of immune checkpoint inhibition combined with intracellular pathway may be the key to solve the problem. The purpose of this study is to prepare SIRPα-TRAIL fusion protein to block the "don't eat me" signal, prevent tumor cell immune escape, and restore the phagocytosis of macrophages to tumor cells; at the same time, triggered cell death can recruit macrophages to phagocytize tumor cells and play a dual anticancer effect. To explore the effect and mechanism of fusion protein from molecular, cell, tissue, animal model and other levels. This not only solves the disadvantages of low activity and adverse reactions of single treatment, but also plays a dual anti-tumor effect, expands the effect of drug treatment, and provides a new idea for the clinical treatment of ovarian cancer.