Tumor cells metabolically resist immune-checkpoint therapy by macrophage efferocytosis-mediated fatty acid recycling

  • Cancer Cell. 2026 Jun 8;44(6):1235-1254.e11. doi: 10.1016/j.ccell.2026.05.005.
Zhixian Liang  1 ,  Xiaohang Long  1 ,  Zhewen Xiong  1 ,  Patrick Pak-Chun Wong  1 ,  Siyuan Huang  1 ,  Siyun Chen  1 ,  Yiling Zhang  1 ,  Lingyun Zhang  1 ,  Chunning Leung  2 ,  Jianquan Cao  1 ,  Haoran Wu  1 ,  Hui Yue  1 ,  Zihui Zhao  1 ,  Yalin Tu  1 ,  Baoyi Yin  1 ,  Weiqin Yang  1 ,  Jing Wang  1 ,  Shufen Chen  1 ,  Xuerao Zhang  1 ,  Yuk Wah Tsang  1 ,  Chengpeng Zhong  3 ,  Xiaoyu Liu  1 ,  Lipeng Ding  1 ,  Jiahuan Lu  1 ,  Willis Wai-Yiu Si-Tou  1 ,  Yan Liu  1 ,  Yaxian Wang  1 ,  Yingnan Lin  1 ,  Jianxin Liang  1 ,  Weida Ren  1 ,  Joaquim Si-Long Vong  1 ,  Man Tong  1 ,  Xiaoyu Tian  1 ,  Hannah Xiaoyan Hui  1 ,  Jingying Zhou  1 ,  Saiming Ngai  2 ,  Shelly Ni  4 ,  Ka-Fai To  4 ,  Thomas Braun  5 ,  Joseph Jao-Yiu Sung  6 ,  Stephen Lam Chan  7 ,  Alfred Sze-Lok Cheng  8
Affiliations
  • 1. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 2. School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 3. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China; Department of Liver Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China.
  • 4. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5. Department of Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore; State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
  • 7. Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: [email protected].
  • 8. School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: [email protected].
PMID: 42259249 DOI: 10.1016/j.ccell.2026.05.005
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.

Keywords
TREM2; efferocytosis; fatty acid metabolism; hepatocellular carcinoma; immune-checkpoint blockade; lipid-associated macrophages.
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