免疫疗法极有可能开创临床肿瘤治疗新局面。针对肿瘤免疫抑制微环境，发展肿瘤免疫增强型药物是热点问题。血管内皮惰性化是肿瘤造就免疫抑制微环境并产生药物抗性的重要机制。TNFa通过活化血管内皮细胞触发瘤内免疫反应而显示超强抗肿瘤活性。但天然TNFa系统毒性强。因此，靶向运输是TNFa广泛临床应用的前提和保障。课题组前期利用一种肿瘤穿透肽与TNFa融合，显著增强其抗肿瘤作用并切实降低了系统毒性。本项目拟进一步筛选更多肿瘤穿透肽，组建系列靶向性TNFa融合蛋白，确定其单独或联合用药的抗肿瘤效果及机制，评价将其发展为新型肿瘤免疫治疗药物的可能性。项目选择的肿瘤穿透肽既有肿瘤靶向性，又有组织穿透性，可将大分子蛋白运输至瘤体深部，显示更强大的抗肿瘤效果。将其与TNFa融合，可望推出系列自主知识产权、靶向性好、机制独特的高效、低毒抗肿瘤蛋白，为实体瘤免疫治疗提供新选择。

Recently, series of progresses made immunotherapy as a breakthrough in clinic cancer therapy. According to the growing knowledge of the immunosuppressive tumor microenvironment, harnessing the immune system to attack tumors became a hot topic in cancer therapy. Allergy of endothelium of tumor vessels is an important mechanism for keeping immunosuppressive tumor microenvironment and induction of drug resistance of tumor. It is known that TNFa exerts superior antitumor activity through intratumoral immune responses triggered by injury or activation of tumor endothelial cells. However, systemic toxicity of natural TNFa is obvious. The premise for application of TNFa in clinic cancer therapy is intratumoral delivery. In our previous works, we have identified a tumor-penetrating peptide which can specifically bind tumor endothelial cells and penetrate into the solid tumor. It was found that fusion to the tumor-penetrating peptide significantly enhanced the antitumor effect, but simultaneously reduced the systemic toxicity of TNFa, which strongly triggered our interesting to deliver TNFa using more tumor-penetrating peptides. In this project, we will extend the screening of tumor-penetrating peptide candidates and produce series of fusion proteins containing tumor-penetrating peptide and TNFa. And we will determine the antitumor effect of these fusion proteins as a monotherapy or in combination with other drugs, followed by investigation of their mechanisms. The systemic toxicity of fusion protein will be evaluated and compared with that of TNFa. In addition, the potential of these fusion proteins as novel agents for cancer immunotherapy will be suggested. Tumor-penetrating peptides used in this project are tumor-targeting as well as tumor-penetrating, which is helpful to deliver the big protein deeper into the solid tumor thus might exert better antitumor effect. By using these peptides as carrier of TNFa, it is possible to develop several fusion proteins with improved antitumor effect but lower toxicity. And these proteins might be novel alternations for immunotherapy of solid tumors.