EXO^TLR1/2-STING: A Dual-Mechanism Stimulator of Interferon Genes Activator for Cancer Immunotherapy.

Abstract

As natural agonists of the stimulator of interferon genes (STING) protein, cyclic dinucleotides (CDNs) can activate the STING pathway, leading to the expression of type I interferons and various cytokines. Efficient activation of the STING pathway in antigen-presenting cells (APCs) and tumor cells is crucial for antitumor immune response. Tumor-derived exosomes can be effectively internalized by APCs and tumor cells and have excellent potential to deliver CDNs to the cytoplasm of APCs and tumor cells. Here, we leverage tumor exosomes as a delivery platform, designing an EXO^TLR1/2-STING loaded with CDNs. To achieve efficient loading of CDNs onto exosomes, we chemically conjugated CDNs with Pam₃CSK₄, a compound featuring multiple fatty acid chains, resulting in Pam₃CSK₄-CDG^SF. Utilizing the high lipophilicity of Pam₃CSK₄, Pam₃CSK₄-CDG^SF could be efficiently loaded onto the exosomes through simple incubation. Moreover, as an agonist for Toll-like receptor 1/2, Pam₃CSK₄ also exhibits robust immunological synergistic effects in conjunction with CDNs. EXO^TLR1/2-STING effectively induced the activation of APCs and triggered tumor cell death, producing a favorable antitumor therapeutic effect. It also demonstrated significant synergistic effects with immune checkpoint therapies.