Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8⁺ T cells. Intriguingly, targeting of the TGF-β trap to PD-L1⁺ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.

局部放疗 (RT) 诱导免疫原性抗肿瘤反应，该反应在一定程度上被免疫逃避和组织重塑过程的激活所抵消，例如，通过上调程序性细胞死亡配体 1 (PD-L1) 和转化生长因子 β (TGF-β ）。我们报告了一种同时抑制 TGF-β 和 PD-L1 的双功能融合蛋白 bintrafusp alfa (BA)，可有效地与放射疗法协同作用，从而在免疫浸润较差的多种抗治疗小鼠肿瘤模型中获得更高的存活率。BA + RT (BART) 组合增加了肿瘤浸润性白细胞，重新编程肿瘤微环境，并减弱 RT 诱导的纤维化，导致肿瘤免疫的重建和自发性肺转移的消退。始终如一，⁺ T 细胞。有趣的是，通过 BA 将 TGF-β 陷阱靶向 PD-L1 ⁺内皮和 M2/脂肪成纤维细胞样细胞区室，可减轻晚期 RT 诱导的肺纤维化。总之，结果表明，BART 组合有可能根除耐药性肿瘤，同时保留正常组织，进一步支持其临床转化。