Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma.

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-07-23 DOI:10.1038/s41467-025-62132-y

Tianhao Chu,Guiqi Zhu,Zheng Tang,Weifeng Qu,Rui Yang,Haiting Pan,Yi Wang,Ruilin Tian,Leilei Chen,Zhiqi Guan,Yichao Bu,Qianfu Zhao,Jiafeng Chen,Shengwei Mao,Yuan Fang,Jun Gao,Xiaoling Wu,Jian Zhou,Weiren Liu,Dan Ye,Jia Fan,Yinghong Shi

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Abstract

The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2+ TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2+ TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8+ T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2+ TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2+ TAMs, offering a promising therapeutic avenue for HCC immunotherapies.

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代谢原型癌细胞在肝细胞癌中通过氧化低密度脂蛋白介导的代谢相互作用诱导tre2 +巨噬细胞。

癌细胞所采用的功能程序及其对肿瘤微环境的影响是复杂的，目前尚不清楚。在这里，我们在肝细胞癌（HCC）细胞中确定了三种不同的单细胞原型（即代谢、干性和炎症），每种细胞都表现出独特的空间分布。进一步的分析表明，由代谢原型癌细胞和TREM2阳性肿瘤相关巨噬细胞（TREM2+ tam）组成的免疫抑制生态位加剧了免疫排斥并损害了患者的预后。在机制上，我们证明了代谢原型癌细胞中角鲨烯环氧化酶（SQLE）表达的上调促进了氧化LDL （oxLDL）的产生。OxLDL通过TREM2- syk - cebp - α轴诱导TREM2+ TAM极化，使这些TAM促进癌细胞侵袭，抵抗效应细胞因子和CD8+ T细胞功能障碍。重要的是，在人和小鼠HCC中，癌细胞固有的SQLE和TREM2+ tam与较差的免疫治疗反应相关。我们的研究结果强调了癌细胞与TREM2+ tam之间的氧化低密度脂蛋白介导的代谢相互作用，为HCC免疫治疗提供了一个有希望的治疗途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.