The immune landscape of hepatocellular carcinoma (HCC) following transarterial chemoembolization (TACE) remains to be clarified. This study aimed to characterize the immune landscape following TACE and the underlying mechanism of HCC progression.Tumor samples from 5 patients with treatment-naive HCC and 5 patients who received TACE therapy were collected and subjected to single-cell RNA sequencing. Another 22 paired samples were validated using immunofluorescence staining and flow cytometry. To clarify the underlying mechanisms, In vitro co-culture experiments and two types of TREM2-KO/WT mouse models, including HCC cell orthotopic injection model and spontaneous HCC model, were used.A reduced number of CD8+ T cells and an increased number of tumor-associated macrophages (TAMs) were observed in the post-TACE microenvironment. TACE therapy reduced the cluster CD8_C4, which was highly enriched with tumor-specific CD8+ T cells of pre-exhausted phenotype. TREM2 was found to be highly expressed in TAMs following TACE, which was associated with a poor prognosis. TREM2+ TAMs secreted less CXCL9 but more Galectin-1(Gal-1) compare to TREM2- TAMs. Gal-1 promoted PD-L1 overexpression in vessel endothelial cells, impeding CD8+ T cells recruitment. TREM2 deficiency also increased CD8+ T cell infiltration, which inhibited tumor growth in both in vivo HCC models. More importantly, TREM2 deficiency enhanced the therapeutic effect of anti-PD-L1 blockade.This study shows that TREM2+ TAMs play an important role in suppressing CD8+ T cells. TREM2 deficiency increased the therapeutic effect of anti-PD-L1 blockade by enhancing anti-tumor activity of CD8+ T cells. These findings explain the reasons for recurrence and progression after TACE and provide a new target for HCC immunotherapy intervention after TACE therapy.Copyright © 2023. Published by Elsevier B.V.