Tumor cells metabolically resist immune-checkpoint therapy by macrophage efferocytosis-mediated fatty acid recycling
Zhixian Liang, Xiaohang Long, Zhewen Xiong, Patrick Pak-Chun Wong, Siyuan Huang, Siyun Chen, Yiling Zhang, Lingyun Zhang, Chunning Leung, Jianquan Cao, Haoran Wu, Hui Yue, Zihui Zhao, Yalin Tu, Baoyi Yin, Weiqin Yang, Jing Wang, Shufen Chen, Xuerao Zhang, Yuk Wah Tsang, Chengpeng Zhong, Xiaoyu Liu, Lipeng Ding, Jiahuan Lu, Willis Wai-Yiu Si-Tou, Yan Liu, Yaxian Wang, Yingnan Lin, Jianxin Liang, Weida Ren, Joaquim Si-Long Vong, Man Tong, Xiaoyu Tian, Hannah Xiaoyan Hui, Jingying Zhou, Saiming Ngai, Shelly Ni, Ka-Fai To, Thomas Braun, Joseph Jao-Yiu Sung, Stephen Lam Chan, Alfred Sze-Lok Cheng
Journal：CANCER CELL
IF：56.1
DOI：10.1016/j.ccell.2026.05.005
PMID：
Published：2026-06-08
research field：肿瘤免疫学免疫治疗分子肿瘤学微环境生物学肿瘤代谢
Abstract
Tumor cells metabolically adapt to the nutrient-deprived tumor microenvironment (TME). However, the metabolic plasticity underlying immune-checkpoint blockade (ICB) adaptation remains unclear. Here, we report that tumor cells exploit macrophage efferocytosis to metabolically counteract immune-checkpoint targeting. Serial tumor biopsies from patients with ICB-resistant hepatocellular carcinoma (HCC) demonstrate heightened tumor cell fatty acid uptake (FAU) with concomitant up-regulation of TREM2+ lipid-associated macrophages (LAMs) in lipid-laden TME. Myeloid-specific Trem2 deficiency and anti-TREM2 antibody abolish fatty acid-dependent energy production in ICB-resistant tumor cells, resensitizing them to ICB via epigenetic TME remodeling. Mechanistically, TREM2+ LAMs recycle fatty acids to tumor cells via efferocytosis-derived extracellular vesicles, thereby promoting H3K36 acetylation-associated activation of MYC and TGF-β signaling. Single-cell spatial analysis supports TREM2+ LAM efferocytosis in the epigenetic immune evasion of patients with ICB-resistant HCC. As high TREM2+ LAMs correlate with FAU and ICB non-responsiveness in multiple human cancers, our study identifies a common metabolic vulnerability for combinatorial immune-checkpoint targeting.
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