Chromosomal Instability Induces Non–Cell-Autonomous Cancer Progression

Chromosomal instability (CIN) has been shown to promote metastasis, with previous studies indicating a role for the cGAS–STING innate immune pathway in this process. However, as these studies were conducted in partially immune-incompetent models, the exact role the immune system plays in CIN-promoted metastasis is not yet known. To determine if the effects of CIN on metastasis is cancer cell autonomous or dependent on the immune system, Li, Hubisz, Earlie, Duran, and colleagues demonstrated that CIN induced the chronic activation of the cGAS–STING pathway, which drives metastasis in a manner dependent on the immune system in models of triple-negative breast cancer (TNBC), colorectal cancer, and melanoma. To understand how CIN-induced STING signaling shapes the tumor microenvironment (TME), an innovative tool called ContactTracing was developed, which harnesses intrinsic biological variability captured by single-cell transcriptomic data to infer how cell–cell interactions regulate transcription in target cells, and its use showed that the TME of CIN^hi tumors was enriched for immune-suppressive macrophages, granulocytic myeloid-derived suppressor cells, and dysfunctional T cells, which could be reversed upon cancer cell loss of Cgas or Sting1 genes. Mechanistically, CIN^hi tumors demonstrated significant enrichment of STING-dependent endoplasmic reticulum (ER) stress response–related genes and subsequent induction of metastasis in an immune system–dependent manner that could be reversed upon STING inhibitor treatment. This suggests that STING inhibition is a potential therapeutic target in tumors with CIN. Additionally, IFN tachyphylaxis, a reduction in IFN responsiveness after repetitive treatment, was also found to occur downstream of STING. Moreover, in human TNBC tumor samples, CIN and widespread cGAS activation were associated with enhanced ER stress–related genes, an immune-suppressive TME, and metastasis. In summary, these results show that CIN rewires downstream STING signaling to promote immune suppression and metastasis and suggest that patients with chromosomally unstable tumors may therapeutically benefit from inhibition of cGAS–STING signaling.

Li J, Hubisz MJ, Earlie EM, Duran MA, Hong C, Varela AA, et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature 2023;620:1080–8.

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