TREM1 + Neutrophils Determine Immunosuppressive Microenvironment and Immunotherapy Response in Hepatocellular Carcinoma

ABSTRACT Background and Aims Hepatocellular carcinoma (HCC) is a highly immunosuppressive cancer with limited treatment options and poor prognosis. Neutrophils, as prominent immune cells in the tumour microenvironment, critically shape disease progression and treatment response. Here, we aimed to identify pivotal neutrophil subsets driving HCC progression. Methods Neutrophil‐specific marker genes were identified through single‐cell RNA sequencing (scRNA‐seq) analyses. The clinical significance of neutrophils with triggering receptor expressed on myeloid cells‐1 (TREM1) positive was assessed in HCC patient cohort by immunofluorescence staining. The immune landscape of HCC and the functional phenotype of TREM1+ neutrophils were further characterised using cytometry by time‐of‐flight (CyTOF). Results scRNA‐seq analyses revealed that TREM1 was mainly expressed in intratumoural neutrophils within the HCC microenvironment. A high abundance of intratumoural TREM1 + neutrophils was significantly associated with poor prognosis in HCC patients. CyTOF profiling demonstrated that HCC tumours enriched with TREM1 + neutrophils exhibited CD8 + T‐cell exclusion and increased infiltration of immunosuppressive macrophages. Moreover, TREM1 + neutrophils exhibited an immunosuppressive functional state. Pharmacological inhibition of TREM1 by VJDT enhanced the therapeutic efficacy of anti‐PD‐1 antibody in HCC preclinical models. Conclusions TREM1 is mainly expressed in neutrophils in HCC and drives the immunosuppressive reprogramming of neutrophils and tumour microenvironment. Infiltration of TREM1 + neutrophils correlates with unfavourable clinical outcomes in HCC. Targeting TREM1 may augment the efficacy of anti‐PD‐1 therapy in HCC.