Synergy of STING and CD40 agonists in DC1-mediated anti-tumor immunity and cancer immunotherapy 9387

Abstract Description Immune checkpoint inhibitors exhibit limited efficacy in metastatic cancers, especially in elderly patients. Innate immune agonists like STING and CD40 agonists have the potential to trigger systemic anti-tumor responses but remain clinically suboptimal. Strategies to fully exploit the therapeutic potential of intratumoral innate immune agonists remain under development. In this study, we demonstrate that intratumoral injection of the STING agonist cGAMP, in combination with CD40 agonists, effectively eradicates distant metastatic tumors in both young and aged mice—an effect not achievable with single-agent therapies. Mechanistically, cGAMP enhances antigen-presenting cell activation and promotes NK cell infiltration, leading to the regression of primary tumors, while CD40 stimulation facilitates DC1 migration to tumor-draining lymph nodes and primes tumor-specific T cells. Notably, the cGAMP-CD40 synergy reprograms the myeloid compartment into a distinct state marked by high production of IL-12, interferons, and GM-CSF. Deletion of CD40 or STING specifically in DC1 cells, rather than in macrophages, abolished these effects and impaired anti-tumor immunity. This reprogramming further promotes the robust induction of T-bet–expressing anti-tumor T cells and NK cells, culminating in effective tumor rejection. These findings reveal a novel localized therapeutic strategy that synergizes with existing immunotherapies and holds promising potential for advancing cancer treatment. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)