PD-L1/PD-1（PD）抗体阻断疗法在临床上展示了良好的治疗效果。然而大多数病人即使肿瘤内检测到淋巴细胞浸润，却不能对PD阻断产生积极的应答。怎样克服对PD阻断疗法的耐受，促进肿瘤的清除是现在十分迫切的任务。我们提出肿瘤内抗原递呈细胞（APC）活化缺陷可能限制了PD阻断介导的肿瘤特异性T细胞激活。局部注射I型干扰素可以恢复抗原递呈,但同时上调抑制性分子PD-L1。我们计划构建IFN-anti-PD-L1的融合蛋白，同时靶向PD-L1阻断和IFNAR信号通路活化，激活肿瘤特异性T细胞。该研究（1）拟通过构建融合蛋白，以anti-PD-L1作为载体将IFNα运输到肿瘤组织，解决细胞因子的肿瘤靶向问题。（2）利用IFNα活化肿瘤内APC，联合PD阻断充分激活T细胞，打破对PD阻断治疗的耐受。本研究将加深对PD阻断治疗耐受机制的理解，对于提高免疫检查点阻断治疗效果和临床应用具有重要的指导意义。

PD-L1/PD-1(PD) blockade therapy demonstrated impressive results in clinic. However, most patients remain unresponsive to intensive PD therapy despite the presence of tumor-infiltrating lymphocytes. It is a critical task to overcome the tolerance to PD blockade therapy and increase the tumor clearance. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1 blockade. Local delivery of type I interferon (IFN) restored antigen presentation but also upregulated PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFN (IFN-anti-PD-L1) targeting both PD-L1 blockade and IFN-alpha receptor (IFNAR) activation within tumor microenvironment, to reactivate the T cells and clear the tumor. In this study(1)through constructing cytokines-Ab fusion protein, ant-PD-L1 is used as a carrier to deliver the IFNα specifically to tumor tissues besides its PD signaling blocking function.(2)Targeting IFNαactivate the APC, and together with PD blockade activate tumor-specific T cells. Such a strategy may break the innate and adaptive resistance of tumor immunity to PD blockade. It will provide important guidance to help design the strategies and modalities to increase the response to PD blockade in clinic.