Next-Generation HER-2 Tumor-Targeted Delivery of the STING Agonist Immune-Stimulating Antibody Conjugate (ISAC) Improves Anticancer Efficacy and Induces Immunological Memory.

Recently, rapidly evolving STING-based immunotherapies have offered novel therapeutic options for various cancer types. However, systemic administration of STING agonists raises safety concerns, and intratumoral injection is constrained by tumor accessibility. Herein we developed an immune-stimulating antibody conjugate (ISAC) that links STING agonists to antibodies that target HER2-positive tumor cells via a cleavable linker. In vivo studies demonstrated that the STING agonist ISAC is well tolerated and exhibits potent antitumor activity in syngeneic mouse tumor models. Investigations in STING-knockout HER2-positive tumor cells and STING-knockout mouse models revealed that the STING pathway primarily mediates antitumor effects upon the activation of immune and tumor cells and that the activation of immune cells plays a stronger role. Additionally, our findings indicate that the STING agonist ISAC enhances both innate and adaptive antitumor immune responses, leading to sustained antitumor activity and the establishment of immune memory. These outcomes support the clinical development of the STING agonist ISACs.