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Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1 + regulatory myeloid (M reg ) cells expressing monocyte- and neutrophil-affiliated genes. THBS1 + M reg cells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1 + M reg cells are CD163 + but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC., Competing Interests: Declaration of interests M.D. is co-founder, chief scientific officer, and employee of Inotrem SA, a French company that develops TREM1 inhibitors., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)