Co-delivery of Phagocytosis Checkpoint Silencer and Stimulator of Interferon Genes Agonist for Synergetic Cancer Immunotherapy

Abstract

Efficient capture and presentation of tumor antigens by antigen-presenting cells (APCs), especially dendritic cells (DCs), are crucial for activating the anti-tumor immunity. However, APCs are immunosuppressed in the tumor microenvironment, which hinders the tumor elimination. To reprogram APCs for inducing strong anti-tumor immunity, we report here a co-delivery immunotherapeutic strategy targeting the phagocytosis checkpoint (signal regulatory protein α, SIRPα) and stimulator of interferon genes (STING) of APCs to jointly enhance their ability of capturing and presenting tumor antigens. In brief, a small interfering RNA targeting SIRPα (siSIRPα) and a STING agonist (cGAMP) were co-delivered into APCs by the encapsulation into poly­(ethylene glycol)-b-poly­(lactide-co-glycolide)-based polymeric nanoparticles (NPsiSIRPα/cGAMP). siSIRPα-mediated SIRPα silence promoted APCs to actively capture tumor antigens by engulfing tumor cells. The cGAMP-stimulated STING signaling pathway further enhanced the functions of APCs, thereby increased the activation and expansion of CD8+ T cells. Using ovalbumin (OVA)-expressing melanoma as a model, we demonstrated that NPsiSIRPα/cGAMP stimulated the activation of OVA-specific CD8+ T cells and induced holistic anti-tumor immune responses by reversing the immunosuppressive phenotype of APCs. Collectively, this co-delivery strategy synergistically enhanced the functions of APCs and can be extended to the treatment of tumors with poor immunogenicity.

Chemical and Biomolecular Strategies for STING Pathway Activation in Cancer Immunotherapy

“…It will be important to consider this emerging information in the design of next-generation STING agonists and delivery technologies. Several groups have already developed systems that allow for codelivery of STING agonists and therapeutics that can target other therapeutic pathways ,,,,, …”

“…To avoid use of chemotherapy while still aiming to enhance tumor antigen uptake by APCs, Lu et al also leveraged a polymeric carrier for dual-delivery of cGAMP and an siRNA to inhibit expression of the phagocytosis checkpoint, signal regulatory protein α (SIRPα). 457 SIRPα is expressed by APCs and binds to the "don't eat me signal", CD47 expressed by cancer cells as an immune evasion mechanism to prevent phagocytosis. The group coloaded cGAMP and siRNA into particles, which had a diameter of ∼100 nm and were comprised of PEG-block-PLGA copolymers and the cationic lipid DOTAP.…”

Targeting the innate immune system with nanoparticles for cancer immunotherapy

“…Using ovalbumin (OVA)-expressing melanoma as a model, it has been demonstrated that NP siSIRPa/cGAMP stimulated the activation of OVA-specific CD8 + T cells and induced holistic anti-tumor immune responses by reversing the immunosuppressive phenotype of APCs. 132 Nanoparticles loaded with STING agonists are also used combination with an immune checkpoint inhibitor or other therapy strategies for cancer treatment. 133 It has been found that lipid nanoparticles containing the STING agonist (STING-LNPs) efficiently induced activation of NK cells and are beneficial for cancer immunotherapy.…”

Poly lactic-co-glycolic acid-based nanoparticles as delivery systems for enhanced cancer immunotherapy

“…The potent adjuvant effect was associated with lymphoid and myeloid cell population alterations in the tumor and tumor-draining lymph node. Lu et al (2021) developed a co-delivery immunotherapeutic strategy of the phagocytosis checkpoint (signal regulatory protein α, SIRPα) silencer and stimulator of interferon genes (STING) of APCs. A small interfering RNA targeting SIRPα (siSIRPα) and a STING agonist (cGAMP) were encapsulation into PLGA-based polymeric nanoparticles using the double emulsification method.…”