M2 macrophage-derived exosomes suppress tumor intrinsic immunogenicity

T-cell-based immune checkpoint blockade therapy (ICB) can be undermined by local immunosuppressive M2-like tumour-associated macrophages (TAMs). This study reported that immunosuppressive M2 macrophages render cancer cells resistant to CD8+ T-cell-dependent tumour-killing refractory ICB efficacy by secreting exosomes. Mechanistically, M2 exosomal ApoE diminished the tumour-intrinsic ATPase activity of binding immunoglobulin protein (BiP) to decrease tumour MHC-I expression. Collectively, the findings signify that the exosome-mediated transfer of functional ApoE from M2 macrophages to the tumour cells confers ICB resistance. Our findings also provide a preclinical rationale for treating M2-enriched tumours with ApoE ligand, EZ-482, to restore sensitivity to ICB immunotherapy.