Programmed cell death protein 1 and Vascular endothelial growth factor in the context of radiotherapy (PD-1/VEGF/RT)

The therapeutic axis involving Programmed cell death protein 1 (PD-1) and Vascular endothelial growth factor (VEGF) in the context of radiotherapy (RT) represents a synergistic approach to cancer treatment. PD-1 is an inhibitory receptor expressed on T cells that maintains self-tolerance but is exploited by tumors to evade immune detection (UniProt: Q15116). VEGF is a key pro-angiogenic cytokine that promotes the formation of disorganized tumor vasculature, which contributes to an immunosuppressive, hypoxic microenvironment (UniProt: P15692). Radiotherapy serves as a catalyst by inducing DNA damage and immunogenic cell death, which releases neoantigens; however, it can also trigger compensatory upregulation of PD-L1 and VEGF (PubMed: 29038211). By combining RT with PD-1 and VEGF inhibitors, clinicians aim to normalize tumor vessels for better immune cell delivery and prevent T-cell exhaustion, potentially leading to enhanced local control and systemic abscopal effects (PubMed: 30104715, PubMed: 28438883). This triple-modality strategy is currently being investigated in numerous clinical trials to overcome resistance in solid tumors such as non-small cell lung cancer and renal cell carcinoma.

Other names

PD-1/VEGF/Radiotherapy axisRadio-immunotherapy and anti-angiogenesis combinationPD-1/VEGF/RT synergistic axis

Radiotherapy induces immunogenic cell death and the release of tumor-associated antigens, effectively priming the immune system. VEGF inhibition normalizes the chaotic tumor vasculature, reducing hypoxia and facilitating the infiltration of cytotoxic T cells into the tumor microenvironment. PD-1 inhibition prevents the exhaustion of these T cells by blocking the inhibitory interaction with PD-L1, which is often upregulated following radiation, thereby sustaining a robust and systemic anti-tumor immune response.