ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver

Abstract Type 1 innate lymphoid cells (ILC1) are abundant in the adult liver and are pivotal for immune surveillance and modulation, but the regulation of their maintenance and functionality remains underexplored. Here, we re-analyze published single-cell RNA- sequencing data and find increased expression of Asb2 in ILC1s from adult mouse livers. Conditional ablation of Asb2 in NKp46 + cells, depleting ASB2 in ILC1s and NK cells, in mice impairs ILC1 survival and reduces adult liver ILC1 numbers. Proteomics and bulk RNA-sequencing reveal enriched lipid metabolism pathways in ASB2-deficient ILC1s, concomitant with increased lipid storage. Importantly, pharmacological inhibition of lipid synthesis prevents the apoptosis of ASB2-deficient ILC1s in vitro. In a mouse model of colorectal cancer liver metastasis, we find increased ILC1 lipid storage, and conditional Asb2 deficiency in ILC1 cells exacerbates liver metastasis progression. Conversely, inhibiting lipid accumulation in wild-type colorectal cancer-bearing mice prolongs animal survival, potentially via promoting ILC1-mediated anti-tumor immunity. Thus, our study uncovers ASB2-regulated lipid metabolism as a gatekeeper for ILC1 homeostatic fitness and tumor surveillance, highlighting potential ILC1-based therapeutic strategies against liver tumors.