阿昔替尼与 PD-L1 siRNA 共递送通过血管正常化和免疫检查点抑制的协同作用增强抗癌免疫

Immune checkpoint inhibition (ICI) has become the mainstay of immunotherapy for the treatment of renal cell carcinoma (RCC).

However, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy and the key reason is that RCC belongs to a vascular-rich tumor for promoting immunosuppression. Specifically, the dysfunctional tumor vasculature hinders effector T cell infiltration and induces immunosuppressive tumor microenvironment via the release of cytokine, which attenuates the therapeutic efficacy of ICI.

Therefore, regulating abnormal tumor vasculature may be a promising strategy to overcome the immunosuppressive microenvironment and enhance ICI therapy.

Here, we propose an NGR peptide-modified actively targeted liposome (Axi/siRNA PD-L1 @NGR-Lipo) to encapsulate the anti-angiogenic agents Axitinib and PD-L1 siRNA to promote tumor vasculature normalization and relieve immune evasion for enhanced anti-tumor immunotherapy.

With NGR-mediated tumor homing and active targeting, Axi/siRNA PD-L1 @NGR-Lipo could act on tumor vascular endothelial cells to inhibit neo-angiogenesis, increase pericyte coverage and vascular perfusion, and normalize the structure and function of tumor blood vessels. Meanwhile, it also enhanced immune effector T cells and NK cells infiltration and reduced the proportion of immunosuppressive T cells including MDSC cells and Tregs, thus improving the tumor immunosuppressive microenvironment.

Moreover, Axi/siRNA PD-L1 @NGR-Lipo reduced the expression of PD-L1 protein in tumor cells, restored the recognition and killing ability of cytotoxic T cells, and relieved immune evasion. As expected, Axi/siRNA PD-L1 @NGR-Lipo displayed superior anti-tumor and anti-metastatic efficacy in mice bearing RCC.

Overall, this study demonstrated the important potential of regulating abnormal tumor vasculature to reshape the immunosuppressive microenvironment and boost ICI therapy, which represents a promising avenue for the synergistic anti-tumor with cancer immunotherapy.