PLAUR + Neutrophils Drive Anti‐PD‐1 Therapy Resistance in Patients with Hepatocellular Carcinoma by Shaping an Immunosuppressive Microenvironment

Hepatocellular carcinoma (HCC) is characterized by an immunosuppressive tumor microenvironment (TME) that limits the efficacy of immune checkpoint inhibitors. However, the role of distinct neutrophil subsets within the TME in mediating tumor resistance to immunotherapy remains poorly understood. Here, the present study reveals that the urokinase-type plasminogen activator receptor (PLAUR)⁺ neutrophils are enriched in immunotherapy non-responders and correlate with poor prognosis. Through multi-omics analyses of clinical cohorts and preclinical models, PLAUR⁺ neutrophils identify as a pivotal driver of immunotherapy resistance by shaping an immunosuppressive TME. Mechanistically, spatial transcriptomics and single-cell RNA sequencing reveal that PLAUR⁺ neutrophils orchestrate immune evasion by CD8⁺ T cell exclusion and macrophage-dependent immune suppression. Through the structure-based virtual screening, a novel PLAUR inhibitor is identified that could reverse the immunosuppressive phenotype of neutrophils. In various in vivo tumor models, PLAUR inhibitor suppresses tumor growth and potentiates the efficacy of anti-programmed cell death protein 1 (PD-1) therapy. These results demonstrate that PLAUR⁺ neutrophils serve as a critical regulator of immunotherapy resistance and targeting PLAUR is a promising strategy to augment the efficacy of anti-PD-1 therapy in HCC.