Metabolism archetype cancer cells induce protumor TREM2+ macrophages via oxLDL-mediated metabolic interplay in hepatocellular carcinoma
Tianhao Chu, Gui‐Qi Zhu, Zheng Tang, Wei‐Feng Qu, Rui Yang, Hongbo Pan, Yì Wáng, 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, Ying–Hong Shi
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. Tumour cells can alter the function and metabolism of immune cells to reduce anti-tumour responses. Here the authors use single cell sequencing of HCC and show three tumour archetypes; metabolism, inflammation and stemness and the metabolism archetype are found in association with TREM+ macrophages which restrict immune cell infiltration into the tumour microenvironment.