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

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.