Targeting MSR1 tumor-associated macrophages enhances the therapeutic efficacy of anti-PD-L1 in hepatocellular carcinoma by suppressing NF-κB pathway activation.

MSR1 tumor-associated macrophages (TAMs) have been implicated in various malignancies; however, their functional role in Hepatocellular carcinoma (HCC) remains poorly defined. This research seeks to clarify the roles of MSR1 TAMs in HCC and their influence on the tumor immune microenvironment. Clinical and experimental data indicate that high levels of MSR1 TAMs correlate with poor prognosis in HCC patients. Transcriptomic analyses and in vitro as well as in vivo functional assays revealed that the immunosuppressive activity of MSR1 TAMs is closely linked to their secretory profile. MSR1 enhances IL-6 secretion by activating the NF-κB signaling pathway, subsequently facilitating the recruitment of myeloid-derived suppressor cells (MDSCs). This cascade diminishes CD8 T cell infiltration and effector function, promoting an immunosuppressive tumor microenvironment. In preclinical models, the simultaneous inhibition of MSR1 and PD-L1 markedly reduced tumor growth more effectively than either treatment alone. Our findings demonstrate that MSR1 TAMs contribute to hepatocellular carcinogenesis through the NF-κB/IL-6 signaling axis by promoting MDSCs accumulation and impairing CD8 T cell responses. Effectively targeting MSR1 TAMs can overcome resistance to anti-PD-L1 therapy, offering a promising new immunotherapeutic approach for HCC.