<p>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 APOE⁺ TAM intensity is highly elevated in ICB non-responder tumours and negatively correlated with CD8⁺ T cell infiltration. Pathway analysis and cell interaction reveal that APOE⁺ TAMs suppress CD8⁺ T cells through signal integration and cholesterol efflux. Furthermore, APOE deficiency in macrophages delays tumour growth and promotes the infiltration of CD8⁺ T 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 APOE⁺ TAMs in the formation of immunosuppressive microenvironments and offer a potential therapeutic target for ICB combined therapy.</p>