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.