This study examined how ICB-resistant hepatocellular carcinoma (HCC) tumor cells exploit TREM2+ lipid-associated macrophages (LAMs) via efferocytosis to maintain fatty acid-dependent energy production, using serial biopsies from ICB-resistant HCC patients alongside mouse models with myeloid-specific *Trem2* deficiency and anti-TREM2 antibody treatment.
TREM2+ LAMs recycle fatty acids to tumor cells through efferocytosis-derived extracellular vesicles, driving H3K36 acetylation-mediated MYC and TGF-β signaling activation; blocking TREM2 (genetic or antibody) abolished fatty acid-dependent tumor energy production and resensitized ICB-resistant tumors to immune-checkpoint therapy. High TREM2+ LAM levels correlated with fatty acid uptake and ICB non-responsiveness across multiple human cancers.
Full text was not available; findings rely partly on correlative single-cell spatial analysis in human biopsies, and causal mechanisms were primarily demonstrated in preclinical models. Generalizability across non-HCC tumor types is inferred from correlative data only.
In ICB-resistant cancers, high TREM2+ LAM infiltration may serve as a biomarker of non-response; anti-TREM2 strategies combined with immune-checkpoint blockade represent a potential combinatorial approach to overcome metabolic resistance and warrant clinical evaluation.
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