肿瘤细胞治疗研究
英文原题：ASB2 inhibits lipid accumulation to promote ILC1 homeostatic fitness and anti-tumor immunity in the mouse liver.
1型固有淋巴细胞（ILC1）在成人肝脏中含量丰富，对免疫监视和免疫调节至关重要，但其维持和功能的调控机制仍未得到充分研究。
1型固有淋巴细胞（ILC1）在成体肝脏中含量丰富，对免疫监视和免疫调节至关重要，但其维持和功能的调控机制仍未被充分探索。在此，我们重新分析已发表的单细胞RNA测序数据，发现成体小鼠肝脏ILC1中Asb2表达增加。在NKp46+细胞中条件性敲除Asb2（从而耗竭ILC1和NK细胞中的ASB2），会损害ILC1的存活并减少成体肝脏ILC1数量。蛋白质组学和bulk RNA测序揭示，ASB2缺陷的ILC1中脂质代谢通路富集，同时伴有脂质储存增加。重要的是，药物抑制脂质合成可在体外阻止ASB2缺陷ILC1的凋亡。在结直肠癌肝转移小鼠模型中，我们发现ILC1脂质储存增加，而ILC1细胞中条件性Asb2缺陷会加剧肝转移进展。相反，在野生型结直肠癌荷瘤小鼠中抑制脂质积累可延长动物生存，可能是通过促进ILC1介导的抗肿瘤免疫。因此，我们的研究揭示了ASB2调控的脂质代谢是ILC1稳态适应性和肿瘤监视的守门人，突出了针对肝脏肿瘤的潜在ILC1靶向治疗策略。
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.
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