Tumor-associated macrophages (TAMs) are key determinants of the immunosuppressive microenvironment in hepatocellular carcinoma (HCC) and critically influence the efficacy of immunotherapy. However, how metabolic regulators shape TAM immunophenotypes and subsequent CD8⁺ T cell dysfunction in HCC remains incompletely understood. Single-cell RNA sequencing data and primary tumor samples from patients with HCC were used to characterize xanthine oxidoreductase (XOR) expression on TAMs, and to clarify the underlying mechanisms mediating the effects of XOR⁺ monocytes/macrophages on CD8⁺ T cells. An in-house small-molecule library was screened to identify compounds capable of modulating XOR activity, followed by mechanistic and therapeutic validation in vivo. We identified a marked downregulation of XOR expression in TAMs within HCC tumors, which was significantly associated with poor clinical outcomes. Mechanistically, loss of XOR disrupted PPARγ signaling and cholesterol homeostasis in macrophages, driving their polarization toward an alternatively activated, immunosuppressive M2 phenotype. XOR-deficient TAMs exhibited an impaired capacity to support CD8⁺ T cell activation through enhancing PD-L1 expression, thereby facilitating tumor progression. Notably, a resveratrol derivative, Res616, directly bound to and stabilized the XOR protein, restoring cholesterol metabolic balance and reversing the immunosuppressive phenotype of TAMs. Therapeutically, targeting XOR with Res616 significantly enhanced intratumoral CD8⁺ T cell responses and synergized with anti-PD-L1 therapy to suppress tumor growth in murine HCC models. Our study identified XOR as a pivotal metabolic checkpoint governing TAM-mediated immunosuppression in HCC. Pharmacological stabilization of XOR to restore macrophage cholesterol homeostasis represented a previously unrecognized strategy to remodel the tumor immune microenvironment and improve the efficacy of immune checkpoint blockade.
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