Differential Response to Local Stimulator of Interferon Genes Agonist Administration in Tumors with Various Stimulator of Interferon Genes Statuses

Background/Objectives: The stimulator of interferon genes (STING) is currently accepted as a relevant target for anti-cancer therapies. Besides encouraging results showing STING agonist-induced tumor growth inhibition, in some types of tumors the effect is less prominent. We hypothesized that higher STING levels in cancer cells and the possibility of its activation determine a greater anti-cancer response. As the local administration of STING agonists induces a systemic reaction, we emphasized the importance of host tumor-induced hematological disruption in the efficiency of the therapeutic response. Methods: We investigated the response to STING stimulation in murine cancer cell lines—melanoma (B16-F10) and breast carcinoma (4T1)—and murine normal cell lines: fibroblast cells (NIH/3T3), endothelial cells (H5V), and macrophages (J774A.1). We assessed STING agonist-induced tumor growth inhibition and the therapy’s impact on the hematological system parameters and systemic cytokine release. Results: Our results underlined the improved therapeutic effect of STING activation in melanoma (B16-F10) over breast carcinoma (4T1) tumors. The outcomes reflected a high dysregulation of the hematological system in mice with developed 4T1 tumors, which may support persistent inflammation and impede STING-induced therapeutic effects. Moreover, among typical cytokines produced following STING activation, CCL2 fold change was the one that increased the most in the serum of B16-F10-bearing mice and differentiated the observed response to the STING agonist between investigated tumor models. Conclusions: The current study provides new evidence of the different responses to STING activation among two poorly immunogenic tumor models. The high abundance of STING in B16-F10 cells and the possibility of its activation is linked with improved therapeutic response in vivo compared to 4T1. The effect also seems to be connected with a less dysregulated hematological system in mice with B16-F10 tumors over mice with 4T1 tumors. This highlighted the need for general insight into tumor-induced local and systemic responses to the efficiency of the proposed therapy.