A preclinical platform that delays activation of the STING innate immune pathway until after antigen translation has begun produced stronger antitumor T-cell responses in mouse models, according to a study published August 19 in Nature Biotechnology. The approach addresses a key obstacle to using STING agonists as mRNA vaccine adjuvants: activating STING too early can trigger interferon signaling that suppresses translation of the antigen-encoding mRNA the vaccine relies on.
The research was led by investigators at Peking University's School of Pharmaceutical Sciences, Peking University Cancer Hospital and Institute, and Peking University First Hospital, with contributions from CSPC Pharmaceutical Group Co., Ltd.
How it works
Conventional mRNA cancer vaccines require time after delivery for cells to translate the encoded tumor antigen. STING activation, meanwhile, generates a powerful innate immune response, including type I interferon signaling, that can inhibit protein translation. Activating the two processes simultaneously can therefore be counterproductive: the adjuvant intended to strengthen the immune response can suppress production of the antigen that the immune system needs to recognize.
The researchers addressed this problem by engineering a lipid nanoparticle (LNP) that co-delivers antigen-encoding mRNA, mRNA encoding an exogenous STING protein, and DMXAA, a small-molecule STING agonist temporarily rendered inactive through a biodegradable chemical linker.
Following cellular uptake, the antigen mRNA can initially be translated while the STING agonist remains inactive. As the linker subsequently degrades, DMXAA is released and activates STING, allowing innate immune stimulation to follow rather than interfere with antigen production. The approach is also designed to concentrate STING activation in cells receiving the LNP, potentially limiting unwanted systemic immune effects.
The researchers used HPV E7 and ovalbumin as model antigens. In mouse tumor models, the platform increased CD8+ and CD4+ T-cell responses, suppressed tumor growth, and prolonged survival compared with conventional approaches in which antigen delivery and STING activation occurred together. The study also reported reduced regulatory B-cell induction and immune-cell apoptosis associated with systemic STING activation, with negligible anti-STING immune responses after treatment.
A significant translational hurdle
The platform remains at an early preclinical stage. DMXAA activates mouse STING but not the human protein, meaning the system used in standard mouse experiments cannot simply be transferred into humans. To address this species-specificity problem, the researchers engineered a human STING variant responsive to DMXAA and conducted additional experiments using humanized STING mouse models and ex vivo human samples.
Whether that engineered receptor strategy can provide comparable temporal and cell-specific control in patients remains an important question before clinical development. The delayed-release linker chemistry will also need to demonstrate sufficiently predictable pharmacology, manufacturing consistency, and safety for human use.