Engineered Salmonella-mediated c-di-AMP delivery activates STING to remodel the tumor microenvironment

The stimulator of interferon genes (STING) pathway is a pivotal mediator of innate immunity that senses microbial cyclic dinucleotides (CDNs) to initiate potent type I interferon (IFN-I) responses and proinflammatory cytokine production. In this study, we developed a novel cancer immunotherapy platform by engineering an attenuated Salmonella Typhimurium ΔppGpp strain (designated SL^disA) to constitutively produce the STING agonist cyclic di-AMP (c-di-AMP). Through comprehensive in vitro and in vivo analyses, we demonstrated that SL^disA preferentially colonizes tumors and induces robust dendritic cell (DC) maturation through STING-dependent IFN-I signaling. This activation cascade promoted significant infiltration and activation of T cells, leading to potent antitumor immunity in CT26 colorectal carcinoma models. Furthermore, SL^disA exhibited synergistic tumor regression when combined with PD-1 blockade. Our findings establish engineered STING-activating bacteria as a transformative approach for cancer immunotherapy, offering: 1) targeted delivery of STING agonists to tumors, 2) reversal of immunosuppressive microenvironments, and 3) synergy with existing checkpoint blockade therapies. This platform addresses critical challenges in the field and presents new opportunities for treating immunotherapy-resistant cancers.