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. • MSR1 + TAMs foster immune suppression and HCC progression. • MSR1 + TAMs impair CD8 + T cells by recruiting MDSCs, suppressing anti-tumor immunity. • MSR1 activates NF-κB to boost IL-6 secretion, driving MDSC recruitment in HCC. • Targeting MSR1 enhances anti-PD-L1 efficacy and serves as a prognostic factor in HCC.