纤维化基质和血管生成肿瘤血管在调节肿瘤免疫中发挥重要作用。我们之前报道了一种合理设计的蛋白质 (ProAgio)，它在一个新位点靶向整合素 αvβ3。 ProAgio 诱导表达高水平整合素的细胞凋亡。肿瘤中激活的癌症相关成纤维细胞 (CAF) 和血管生成内皮细胞 (aEC) 均表达高水平的整合素 αvβ3。 ProAgio 同时且特异性地诱导肿瘤中 CAF 和 aEC 的细胞凋亡。我们在这里提供的证据表明，ProAgio 消耗 CAF 和消除渗漏的肿瘤血管生成血管会改变肿瘤免疫。 ProAgio 减少 CD4 Treg 和骨髓源性抑制细胞 (MDSC)，增加 CD8 T 细胞，并增加肿瘤中的 M1/M2 巨噬细胞比率。 ProAgio 消耗致密纤维化基质 (CAF) 会降低肿瘤周围基质区域的程序性死亡配体 1 (PDL-1) 水平，从而大大增加抗 PDL-1 抗体向靶癌细胞的递送。 ProAgio 对肿瘤免疫的影响为检查点抑制剂对肺癌治疗提供了强大的协同作用。

Fibrotic stroma and angiogenic tumor vessels play an important role in modulating tumor immunity. We previously reported a rationally designed protein (ProAgio) that targets integrin αvβ3 at a novel site. ProAgio induces the apoptosis of cells that express high levels of the integrin. Both activated cancer-associated fibroblasts (CAFs) and angiogenic endothelial cells (aECs) in tumors express high levels of integrin αvβ3. ProAgio simultaneously and specifically induces apoptosis in CAFs and aECs in tumors. We provide evidence here that the depletion of CAFs and the elimination of leaky tumor angiogenic vessels by ProAgio alter tumor immunity. ProAgio reduces CD4+ Treg and Myeloid-derived suppressor cells (MDSCs), increases CD8+ T-cells, and increases the M1/M2 macrophage ratio in the tumor. The depletion of dense fibrotic stroma (CAFs) by ProAgio decreases the Programmed Death Ligand 1 (PDL-1) levels in the stroma areas surrounding the tumors, and thus strongly increases the delivery of anti-PDL-1 antibody to the target cancer cells. The impact of ProAgio on tumor immunity provides strong synergistical effects of checkpoint inhibitors on lung cancer treatment.