Abstract 6785: Evasion of hepatic ILC1 immunosurveillance drives breast cancer liver metastasis

Abstract Metastasis is a complex biological process and the principal cause of cancer-related mortality. With dual blood supply and fenestrated sinusoids, the liver’s haematogenous route uniquely favors seeding by circulating tumor cells (CTCs). Nonetheless, while portal drainage promotes frequent liver metastases from proximal gastrointestinal cancers such as colorectal carcinoma, hepatic colonization by systemically disseminated CTCs, including those originating from breast cancer, is highly inefficient. The cellular barriers and evasion mechanisms that govern this selective vulnerability remain poorly understood. Here we show that hepatic type 1 innate lymphoid cells (ILC1s) are selectively required for the immunosurveillance of breast cancer liver metastasis, the evasion of which is driven by both cancer cell-intrinsic and microenvironment-associated immune mechanisms. In a large patient cohort, liver metastasis occurred at a relatively later stage and was associated with poorer survival, with body mass index (BMI) above the WHO optimal range associated with higher risk. This metabolic vulnerability was recapitulated in a murine preclinical model, in which breast cancer CTC colonization of the liver—but not the lung—was promoted by a high-fat diet that induced hepatic steatosis. Mechanistically, NK cells expanded and activated in response to CTC challenge and employed both lytic granule and death receptor 5 (DR5, encoded by Tnfrsf10b) pathways for cancer cell clearance, hepatic ILC1s preferentially utilized DR5-mediated mechanisms and required high DR5 expression in cancer cells. Notably, loss of heterozygosity of TNFRSF10B in breast tumours was associated with a predisposition to liver metastasis, and poorer patient prognosis. Conversely, metabolic dysfunction-associated steatotic liver disease (MASLD), a pathological risk factor for breast cancer liver metastasis, correlated with depletion of hepatic group 1 innate lymphoid cells—a phenomenon recapitulated in high-fat diet-fed mice. Importantly, the high-fat diet-induced reduction in hepatic ILC1s and enhancement of breast cancer liver metastasis were reversed by treatment with glucagon-like peptide-1 (GLP-1) receptor agonists. Collectively, these findings reveal that breast cancer liver metastasis is primarily restrained by liver-resident ILC1s rather than circulating NK cells. Evasion of this immunosurveillance can arise from cancer cell-intrinsic genomic alterations that compromise DR5 sensitivity or from microenvironmental metabolic perturbations that diminish ILC1 function. Restoration of hepatic ILC1 activity by GLP-1 receptor agonists highlights a potential translational opportunity to extend these agents beyond metabolic disease into oncology, with innate lymphocyte-mediated cancer immunosurveillance as a distinct mechanism of action. Citation Format: Peng Li, Jun Li, Andrew Cornish, Jing Zhang, Xian Zhang, Ming Li, . Evasion of hepatic ILC1 immunosurveillance drives breast cancer liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6785.