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Background Immune checkpoint inhibitors have shown promise in treating hepatocellular carcinoma (HCC), yet response rates remain limited. While most studies focus on T cell-based immunotherapy, the potential of natural killer (NK) cells in cancer immunotherapy remains underexplored.Methods Using patient-derived HCC samples, various murine tumor models, and human NK cell-reconstituted xenografts, we examined CXCR1 expression on tumor-infiltrating NK cells and its impact on tumor progression. We employed multi-color immunohistochemistry, single-cell RNA sequencing, and 3D-printed tumor organoids to characterize CXCR1’s spatial distribution and functional effects. Genetic deletion or antibody-mediated blockade of CXCR1 significantly enhanced anti-tumor immunity by preventing NK cell exhaustion and improving NK cell infiltration into tumors. We developed a high-affinity anti-CXCR1 nanobody that demonstrated superior tumor penetration compared to conventional antibodies.Results Notably, CXCR1 blockade outperformed PD-1 inhibition in controlling tumor growth and prolonging survival in our models. Mechanistically, CXCR1 suppressed NK cell migration and effector functions by modulating chemokine signaling potentially ( figure 1). Importantly, the nanobody exhibited favorable safety profiles with no significant toxicity across multiple organ systems.Conclusions These findings establish CXCR1 as a clinically relevant checkpoint regulator and introduce nanobody-based targeting as a promising strategy for enhancing NK cell-mediated cancer immunotherapy.Abstract 437 Figure 1CXCR1 is expressed specifically in tumor infiltrating NK cells with spatial heterogeneity; Genetic deletion of CXCR1 overcome NK exhaustion in Hepatocellular Carcinoma; Anti-CXCR1 therapy inhibits tumor growth in combination with PD1 immunotherapy