Targeting dual gene delivery nanoparticles overcomes immune checkpoint blockade induced adaptive resistance and regulates tumor microenvironment for improved tumor immunotherapy

Abstract Despite the unparalleled tumor growth inhibition and significantly prolonged survival achieved by immune checkpoint blockade (ICB) therapy, more and more adaptive resistance to ICB therapy in clinical practice put patients at risk of uncontrollable tumor growth and tumor relapse. Hence, in this work, we constructed a targeting dual gene delivery system loading pshVEGF-A and pshPD-L1 against murine melanoma to overcome adaptive resistance for efficacious anti-tumor immunotherapy. We reported immune checkpoint blockade by PD-L1 gene silencing induced adaptive resistance through the VEGF-A/VEGF-R2 signal pathway. Therefore, the combination of PD-L1 and VEGF-A gene silencing eliminated adaptive resistance to ICB therapy. Besides, pshVEGF-A as an antiangiogenic agent achieved tumor vessel normalization and reprogramed tumor immune microenvironment towards an immune-supportive profile, synergizing with pshPD-L1 for significant tumor inhibition. This revolutionary dual gene therapy strategy contributed to the diversity of immune combination therapy and had a potential for clinical application in the near future.