A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68⁺ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8⁺ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4⁺ and CD8⁺ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8⁺ T cells in HCC.

Thrombospondin-1 (THBS1) activates latent transforming growth factor-β1 (TGF-β1) and contributes to stromal- immune communication. However, how THBS1 derived from fibroblasts and macrophages collectively contributes to fibroinflammatory remodeling in metabolic dysfunction-associated steatohepatitis (MASH) has not been clearly defined. THBS1 expression was examined in liver tissue and serum from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and in two dietary murine MASH models. We integrated single-cell RNA sequencing, immunohistochemistry, confocal microscopy, and flow cytometry with targeted perturbation of fibroblasts and macrophages using nintedanib, the THBS1-blocking peptide LSKL, and siRNA-mediated THBS1 silencing. THBS1 and the fibroblast activation marker fibroblast activation protein (FAP) increased in association with fibrosis severity and interleukin-6 (IL-6) levels. Single-cell RNA sequencing and spatial imaging demonstrated THBS1 expression in both FAP+ fibroblasts and monocyte-derived macrophages, indicating a coordinated fibroinflammatory niche. Nintedanib reduced THBS1 expression in both compartments, decreased CD11b+MERTK+ macrophages and FAP+PD-L1+ fibroblasts, and improved histologic fibrosis. Direct THBS1 inhibition produced similar antifibrotic effects. In vitro, THBS1 knockdown or blockade suppressed TGF-β1-induced fibroblast activation and reduced lipopolysaccharide-stimulated IL-1β and IL-6 production in macrophages, supporting reciprocal THBS1-dependent stromal-immune signaling. THBS1 functions as a shared signaling mediator between fibroblasts and macrophages in MASH. Therapeutic suppression of THBS1, either through nintedanib or direct inhibition, disrupts this fibroinflammatory circuit and may represent a viable strategy to limit fibrosis progression in MASLD/MASH.

Immunoglobulin A (IgA) connects mucosal defense with hepatic immune regulation, but its effects vary by anatomical compartment, antibody properties, and responding cell type. This narrative review synthesizes experimental and clinical evidence on the gut–liver IgA axis in alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, and hepatocellular carcinoma. We distinguish IgA-producing cells from secreted antibodies and IgA-responsive cells and examine antibody production, cellular trafficking, hepatic clearance, and biliary export. Experimental studies demonstrate the protective effects of mucosal IgA delivery and the context-dependent contributions of IgA-associated responses to inflammation, fibrosis, and impaired antitumor immunity. Human studies identify tissue and prognostic associations but do not establish a common intestinal source of pathogenic hepatic IgA. Collectively, these findings provide a rationale for investigating disease-specific, compartment-directed approaches targeting antibody production, cellular trafficking, protective export, or local effector responses. Clinical translation requires validation of causal mechanisms and intervention-specific biomarkers, as well as evidence of improved liver outcomes while preserving mucosal protection.