Targeting Myeloid Trem2 Reprograms the Immunosuppressive Niche and Potentiates Checkpoint Immunotherapy in NASH-Driven Hepatocarcinogenesis

Abstract Macrophages expressing Trem2 play a pivotal role in promoting non-alcoholic steatohepatitis (NASH; also known as metabolic dysfunction–associated steatohepatitis, MASH) progression to hepatocellular carcinoma (HCC). Despite the widespread clinical use of anti-PD1 immune checkpoint blockade, its therapeutic efficacy in NASH-driven HCC remains suboptimal. This study investigates the mechanisms by which NAM Trem2 influences the response of NASH-driven HCC to immunotherapy. Clinical analysis revealed that elevated Trem2 expression in NASH is positively correlated with accumulation of neutrophil extracellular traps (NET) and infiltration of PD1+Eomes+CD8+ T cells and regulatory T cells (Tregs). Myeloid-specific knockout of Trem2 (Trem2Δmye) led to impaired macrophage reprogramming, resulting in the accumulation of pro-inflammatory Ly6ChiCX3CR1lo macrophages, which enhanced degradation of NETs in NASH. Trem2Δmye also disrupted TGF-β production via P-Syk-dependent efferocytosis, collectively suppressing the differentiation of PD1+Eomes+CD8+ T cells and Tregs. The efficacy of anti-PD1 therapy in inhibiting NASH-driven HCC progression was also significantly enhanced by Trem2Δmye, primarily through the downregulation of Treg CXCR4 expression mediated by increased NET degradation. These therapeutic effects were further amplified when combined with the CXCR2 inhibitor AZD5069. Our findings identify Trem2 as a central regulator of the NASH-driven HCC immunosuppressive niche, and suggest a combinatorial therapeutic strategy that targets both myeloid reprogramming and NETosis to overcome immunotherapy resistance in metabolic liver cancer progression.