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.
背景/目的：干扰素基因刺激因子（STING）目前被公认为抗癌治疗的重要靶点。尽管STING激动剂在抑制肿瘤生长方面展现出令人鼓舞的效果，但在某些类型肿瘤中其作用并不显著。我们假设癌细胞中较高的STING水平及其激活可能性决定了更强的抗癌反应。鉴于STING激动剂的局部给药会引发全身性反应，我们特别强调了宿主肿瘤诱导的血液系统紊乱对治疗反应效率的重要影响。 方法：本研究检测了小鼠癌细胞系（黑色素瘤B16-F10和乳腺癌4T1）及正常细胞系（成纤维细胞NIH/3T3、内皮细胞H5V和巨噬细胞J774A.1）对STING刺激的反应。我们评估了STING激动剂诱导的肿瘤生长抑制效果，以及治疗对血液系统参数和全身性细胞因子释放的影响。 结果：研究结果凸显了STING激活在黑色素瘤（B16-F10）中比在乳腺癌（4T1）中具有更显著的治疗效果。数据显示，4T1肿瘤小鼠的血液系统存在高度失调，这可能维持持续性炎症状态并阻碍STING诱导的治疗效应。此外，在STING激活后产生的典型细胞因子中，CCL2的倍数变化在B16-F10荷瘤小鼠血清中增幅最大，这一指标在不同肿瘤模型中对STING激动剂的反应差异具有鉴别意义。 结论：本研究为两种低免疫原性肿瘤模型对STING激活的不同反应提供了新证据。与4T1相比，B16-F10细胞中STING的高表达及其激活可能性与体内治疗反应的改善相关。这种效应似乎还与B16-F10荷瘤小鼠相比4T1荷瘤小鼠具有更轻微的血液系统失调有关。这凸显了需要全面认识肿瘤诱导的局部和全身反应对治疗方案有效性的影响。
肿瘤(癌症)患者之家