APOE deficiency triggers anti-tumour activity of macrophages in liver cancer.

Abstract

Macrophage infiltration correlates with poor prognosis in patients with liver cancer and resistance to immunotherapy. However, it is difficult to target tumour-associated macrophages (TAMs) because of their inherent heterogeneity. Specific TAM subsets may exhibit distinct functions in tumorigenesis. Herein, we identify a TAM subset characterised by elevated APOE expression, which is correlated with poor overall survival of patients with HCC. The APOETAM intensity is highly elevated in ICB non-responder tumours and negatively correlated with CD8T cell infiltration. Pathway analysis and cell interaction reveal that APOETAMs suppress CD8T cells through signal integration and cholesterol efflux. Furthermore, APOE deficiency in macrophages delays tumour growth and promotes the infiltration of CD8T cells. Using an immunotherapy-resistant mouse model, we showed that APOE blockade synergises with anti-PD-1 therapy and inhibits tumour growth. Our results elucidate the crucial role of APOETAMs in the formation of immunosuppressive microenvironments and offer a potential therapeutic target for ICB combined therapy.