Evasion of Hepatic ILC1 Immunosurveillance Drives Breast Cancer Liver Metastasis

Metastasis, the dissemination of cancer cells to distant organs, is an inefficient process ¹ , yet remains the leading cause of cancer-related mortality ² . The cellular barriers and evasion mechanisms governing organ-specific susceptibility remain incompletely understood ^3–5 , hindering the development of effective anti-metastatic therapies ⁶ . Here, we show that liver-resident type 1 innate lymphoid cells (ILC1s) constitute an essential immunosurveillance barrier against breast cancer liver metastasis that can be bypassed through either cancer cell-intrinsic or host-dependent mechanisms. In a cohort of patients with multi-organ metastatic breast cancer, liver metastasis occurred later and was associated with poorer survival than lung metastasis, with elevated body mass index emerging as a clinical risk factor. This metabolic vulnerability was recapitulated in mice, where a high-fat diet induced hepatosteatosis and selectively enhanced breast cancer colonization of the liver. Mechanistically, liver and lung colonization were restrained by ILC1s and circulating natural killer (NK) cells, respectively. Following cancer cell challenge, NK cells expanded and became activated, clearing cancer cells through the lytic granule pathway and engagement of the death receptor DR5, whereas activated ILC1s selectively required high DR5 expression on cancer cells, supported by AP-2α (TFAP2A)-mediated transcriptional activation, for effective immunosurveillance. Heterozygous copy-number deletion at TNFRSF10B (encoding DR5) in human tumours reduced DR5 expression and predisposed to liver metastasis. Hepatosteatosis further compromised this barrier by reducing IL-15 expression in macrophages, thereby depleting hepatic ILC1s, effects reversible with glucagon-like peptide-1 (GLP-1) receptor agonists. Thus, hepatic ILC1s form a critical organ-specific barrier to breast cancer metastasis, vulnerable to both cancer cell-intrinsic DR5 downregulation and host metabolic dysfunction, the latter of which is pharmacologically correctible.