Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1⁺ ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8⁺ T cells and induced CD8⁺ T-cells apoptosis. Biological and functional assays showed that TREM-1⁺ TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1⁺ TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1⁺ TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1⁺ TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1⁺ TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-κβ pathway in response to hypoxia and tumor metabolites leading to CCR6⁺ Foxp3⁺ Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6⁺ Foxp3⁺ Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6⁺ Foxp3⁺ Treg recruitment was crucial for TREM-1⁺ TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1⁺ TAMs attracting CCR6⁺ Foxp3⁺ Tregs, and TREM-1⁺ TAMs endowed HCC with anti-PD-L1 therapy resistance.

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