尽管肿瘤冷冻消融在直接杀灭肿瘤和原位整细胞肿瘤疫苗注射方面具有潜在的应用价值，但其临床效果却极其不稳定和难以预测，限制了其在临床中的实用性。目前，冷冻消融引发的局部抗肿瘤免疫和相关的远隔效应的机制还不太清楚。本研究的目标是通过鉴定和探索一个机制，阐明冷冻消融如何增强转移性肿瘤模型的治疗效果。我们在C57BL/6或STING-/- (TMEM173-/- )小鼠中使用腹内植入的肌肉肉瘤（RMS）细胞系RMS 76-9STINGwt或RMS 76-9STING-/-及其他小鼠肿瘤模型，评估局部肿瘤变化、肺转移、对远隔肿瘤的远隔效应以及肿瘤微环境（TME）中的免疫细胞动态变化。结果显示，冷冻消融的疗效依赖于适应性免疫和STING信号通路。与当前文献所述宿主源性STING激活在体内驱动抗肿瘤免疫的重要角色相反，我们发现本地肿瘤控制、肺转移和远隔肿瘤的远隔效应都严重依赖于功能正常的肿瘤细胞内在STING信号通路，该通路在冷冻消融的肿瘤微环境中诱导炎性趋化因子和细胞因子反应。这种依赖性不仅限于冷冻消融，还包括肿瘤内STING激动剂治疗。此外，对基因表达数据库和临床肿瘤样本的组织微阵列进行调查揭示了STING相关信号组分表达的广泛变化。肿瘤细胞内在的STING信号通路是实现冷冻消融有效性的关键组成部分，并且提供了STING相关信号组分的表达可能作为潜在的治疗反应生物标志物的线索。我们的数据也强调了进一步研究肿瘤细胞内在的STING信号途径和受冷冻消融和其他依赖于STING的治疗方法诱发的下游炎性反应的迫切需要。© 作者（或其雇主）2023。在CC BY-NC许可下再使用。不得进行商业再使用。由BMJ出版。

Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood.The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9STINGwt or RMS 76-9STING-/-, along with other murine tumor models, in C57BL/6 or STING-/- (TMEM173-/- ) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME).The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components.Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.