染色体不稳定性（CIN）是癌症转移的驱动因素1-4，然而这种影响在多大程度上依赖于免疫系统仍然未知。使用最新开发的、经验证和基准化的ContactTracing工具来推断细胞间相互作用的性质和条件依赖关系，我们发现CIN诱导的cGAS-STING通路的慢性激活促进了癌细胞下游信号的重连，从而导致促转移的肿瘤微环境。这种重连表现为STING下游的I型干扰素快速亚脱敏以及相应增加的由癌细胞源ER应激反应。逆转CIN、消减癌细胞STING或抑制ER应激反应信号可以消除CIN对肿瘤微环境的依赖性效应，并且在免疫功能正常但严重免疫损害的情况下抑制转移。STING抑制剂的治疗可减少黑色素瘤、乳腺癌和结直肠癌的CIN驱动转移，并且依赖于肿瘤细胞内在的STING。最后，我们展示CIN和微核中广泛的cGAS激活与ER应激信号、免疫抑制和人类三阴性乳腺癌的转移相关，突显了一种可行的策略来鉴定和治疗由CIN诱导炎症引发的肿瘤。© 2023. 作者。

Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.© 2023. The Author(s).