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The PD-1/PD-L1 axis represents a well-established immunotherapeutic target. Nevertheless, anti-PD-1/PD-L1 therapeutics have shown limited efficacy in the management of solid tumors, particularly in the context of hepatocellular carcinoma (HCC). Among the various factors contributing to the resistance to anti-PD-1/PD-L1 therapy, tumor-associated macrophages (TAMs) have attracted significant interest because of the immunosuppressive properties. NPLOC4 has been explored as an antitumor drug target. However, whether NPLOC4 functions in TAMs or immunotherapy is unclear. Here, we report a new role for NPLOC4⁺ TAMs in inhibiting antitumor immune responses by facilitating the proteasomal degradation of RIG-I. Clinical specimens revealed that the number of NPLOC4⁺ TAMs are negatively correlated with the prognosis of patients with HCC. Proteomic data and in vitro/in vivo experiments demonstrated that NPLOC4 inhibits the type I interferon pathway in TAMs, promotes M2 polarization, and suppresses CD8⁺ T-cell infiltration, thereby creating an immunosuppressive microenvironment in HCC. NPLOC4 can bind to RIG-I and mediate its ubiquitination-mediated degradation, thus suppressing the type I interferon pathway. Animal studies have indicated that disulfiram/copper (DSF/Cu) can target the NPLOC4 protein, and that the combination of DSF/Cu with PD-1 therapy significantly inhibits HCC growth. In conclusion, targeting NPLOC4⁺ TAMs can significantly increase the resistance of HCC to anti-PD-1 therapy, which makes it a promising novel immune target for HCC treatment.