Lung cancer is the leading cause cancer-related deaths, posing a serious threat to human health worldwide [1]. Non-small cell lung cancer (NSCLC) is a kind of highly malignant tumor with a dismal prognosis, accounting for 80%–85% of lung cancers [2]. Vasculogenic mimicry (VM) is a novel tumor vascular modality distinct from angiogenesis, Which has been shown to be associated with progression, invasion, metastasis, and poor prognosis in tumor patients [3,4]. According to the classical theory of angiogenesis, tumor angiogenesis occurs in two ways: one is angiogenesis and the other is vasculogenesis. Unlike blood vessels composed of endothelial cells, VM is a microvascular channel composed of tumor cells, and the wall of VM usually has a PAS-positive basement membrane-like material lined with tumor cells. Because there is no lining of vascular endothelial cells, under the impact of blood flow, tumor cells are easy to escape from the mother into the circulatory system, resulting in metastasis. In addition, the VM is connected to the host's microcirculatory system, providing sufficient blood supply for tumor growth [5,6]. Despite the extensive application of traditional antiangiogenic drugs in clinical practice prior to the discovery of VM, they failed to achieve an ideal efficacy in treatment. General anti-angiogenic drugs can only inhibit endothelial cell-dependent blood vessels, showing little effect on tumor cells [7]. In addition, studies have shown that anti-angiogenic drugs can cause insufficient blood supply, leading to tumor hypoxia, which in turn promotes the formation of VMs [8]. VM has been shown to occur in multiple aggressive cancers, including breast cancer [9], hepatocellular carcinoma [10], esophageal cancer [11], and ovarian cancer [12]. Anti-VM therapy gradually showcase its significance with the discovery of VMs in different tumors.

More recently, immunotherapy with PD-1 or PD-L1 has significantly improved the prognosis of various tumors, including NSCLC [[13], [14], [15]]. PD-1/PD-L1 inhibitor monotherapy and PD-1/PD-L1 inhibitor combination chemotherapy have become standard care for advanced NSCLC [16]. PD-1 is an important immune checkpoint receptor, mainly presenting on the surface of activated T cells, B cells and macrophages. PD-L1 is expressed not only on the surface of tumor cells, but also on T cells, macrophages, and fibroblasts. PD-L1 of tumor cells inhibits T cell proliferation and differentiation, and initiates immune escape when binding to the PD-1 receptor on T cells [17,18]. High expression of PD-L1 promotes the angiogenesis in tumor tissues [19].

EMT is an important process in which epithelial cells lose their polarity and transform into mesenchymal cells, which is crucial for inducing morphological changes in embryonic development, wound healing, organ fibrosis, and tumor metastasis [[23], [24], [25]]. This process is reversible since mesenchymal cells can differentiate into epithelial cells or other cells [26]. EMT progression and VM are responsible for metastasis, increased risk of tumor recurrence, and shortened survival in cancer patients [27].

In a long-term follow-up of melanoma patients, studies have found the formation of VMs in tumor cells with high PD-L1 expression in the tumor body [20]. Kuma et al. [21],demonstrated that anti-PD-L1 antibodies could reduce the expression of PD-L1 in tumors using PET technology. According to Ma et al. [22],compared with the blank microbubbles(B-MBs), the PD-L1 expression was significantly downregulated in the Anti-PD-L1 monoclonal antibody (mAb)-conjugated ultrasound (US) lipid-shelled microbubbles (PD-L1-MBs) and tumor growth was reduced through the detection of immunofluorescence methods. However, it has not been reported whether anti-PD-L1 antibodies affect the formation of VM in NSCLS. This study investigated the effect and possible mechanisms of anti-PD-L1 antibody on the formation of angiogenesis mimicry in non-small cell lung cancer.