Dual-Responsive Nanomedicine Activates Programmed Antitumor Immunity through Targeting Lymphatic System

Abstract

Effective antitumor immunotherapy depends on evoking a cascade of cancer-immune cycles with lymph nodes (LNs) as the initial sites for activating antitumor immunity, making drug administration through the lymphatic system highly attractive. Here, we describe a nanomedicine with dual responsiveness to pH and enzyme for a programmed activation of antitumor immune through the lymphatic system. The proposed nanomedicine can release the STING agonist diABZI-C2-NH 2 in the LNs' acidic environment to activate dendritic cells (DCs) and T cells. Then, the remaining nanomedicine hitchhikes on the activated T cells (PD-1 + T cells) through binding to PD-1, resulting in an effective delivery into tumor tissues owing to the tumor-homing capacity of PD-1 + T cells. The enzyme matrix metalloproteinase-2 (MMP-2) being enriched in tumor tissue triggers the release of PD-1 antibody (aPD-1) which exerts immune checkpoint blockade (ICB) therapy. Eventually, the nanomedicine delivers a DNA methylation inhibitor GSK-3484862 (GSK) into tumor cells, and then the latter combines with granzyme B (GZMB) to trigger tumor cell pyroptosis. Consequently, the pyroptotic tumor cells induce robust immunogenic cell death (ICD) enhancing the DCs maturation and initiating the cascading antitumor immune response. Study on a 4T1 breast tumor mouse model demonstrates the prominent antitumor therapeutic outcome of this nanomedicine through creating a positive feedback loop of cancer-immunity cycles including immune activation in LNs, T cell-mediated drug delivery, ICB therapy, and tumor cell pyroptosis-featured ICD.

Lymphoid organ-targeted nanomaterials for immunomodulation of cancer, inflammation, and beyond

“…103 In a recent study, Xiao et al developed a dual-action nanomedicine platform that delivers STING in response to the acidic environment in the lymph nodes and triggers the release of PD-1 antibodies in the presence of tumor enzymes, thus activating DCs and T cells and initiating cascading antitumor immune responses. 104 In another example, Lee et al demonstrated that the intramuscular administration of nanoformulated naphthalocyanines successfully enabled precise imaging of lymphatic drainage systems. This finding showcases their potential for cancer diagnosis and therapy in clinical applications.…”