Antibodies targeting the programmed cell death protein 1/programmed cell death ligand-1 (PD-1/PD-L1) pathway have dramatically changed the treatment landscape of advanced non-small cell lung cancer (NSCLC). However, combination approaches are required to extend this benefit beyond a subset of patients. In addition, it is of equal interest whether these combination therapy can be applied to neoadjuvant therapy of early-stage NSCLC. In this study, we hypothesized that combining immunotherapy with anti-angiogenic therapy may have a synergistic effect in local tumor control and neoadjuvant therapy. To this end, the effect of combination of bevacizumab and pembrolizumab in humanized mouse models was evaluated. Furthermore, we innovatively constructed a neoadjuvant mouse model that can simulate postoperative recurrence and metastasis of NSCLC to perform neoadjuvant study. Tumor growth and changes in the tumor vasculature, along with the frequency and phenotype of tumor-infiltrating lymphocytes, were examined. Additionally, in vivo imaging system (IVIS) was used to observe the effect of neoadjuvant therapy. Results showed that combination therapy could inhibited tumor growth by transforming tumor with low immunoreactivity into inflamed (‘hot’) tumor, as demonstrated by increased CD8⁺granzyme B⁺ cytotoxic T cell infiltration. Subsequent studies revealed that this process is mediated by vascular normalization and endothelial cell activation. IVIS results showed that neoadjuvant therapy can effectively prevent postoperative recurrence and metastasis. Taken together, these preclinical studies demonstrated that the combination of bevacizumab and pembrolizumab had a synergistic effect in both advanced tumor therapy and neoadjuvant setting and therefore provide a theoretical basis for translating this basic research into clinical applications.

靶向程序性细胞死亡蛋白 1/程序性细胞死亡配体-1 （PD-1/PD-L1） 通路的抗体极大地改变了晚期非小细胞肺癌 （NSCLC） 的治疗格局。然而，需要联合方法将这种益处扩展到患者亚群之外。此外，这些联合治疗是否可以应用于早期 NSCLC 的新辅助治疗也同样值得关注。在这项研究中，我们假设免疫治疗与抗血管生成治疗相结合可能在局部肿瘤控制和新辅助治疗中产生协同作用。为此，评估了贝伐珠单抗和 pembrolizumab 联合治疗在人源化小鼠模型中的效果。此外，我们创新性地构建了一种新辅助小鼠模型，可以模拟 NSCLC 的术后复发和转移以进行新辅助研究。检查肿瘤生长和肿瘤脉管系统的变化，以及肿瘤浸润淋巴细胞的频率和表型。此外，采用体内成像系统 （IVIS） 观察新辅助治疗的效果。结果显示，联合治疗可以通过将免疫反应性低的肿瘤转化为发炎（“热”）肿瘤来抑制肿瘤生长，CD8 ⁺ 颗粒酶 B ⁺ 细胞毒性 T 细胞浸润增加证明了这一点。随后的研究表明，这个过程是由血管正常化和内皮细胞活化介导的。IVIS 结果显示，新辅助治疗可有效预防术后复发和转移。 综上所述，这些临床前研究表明，贝伐珠单抗和 pembrolizumab 的组合在晚期肿瘤治疗和新辅助治疗中均具有协同作用，因此为将这一基础研究转化为临床应用提供了理论基础。