Fig. 7: Pathological relevance of RNase1, CD206, CD8, and PD-L1 expression in HCC patients.

a–c Quantification of immunohistochemical staining for the correlation between RNase1 and CD206 (a), RNase1 and CD8 (b), and RNase1 and PD-L1 (c) expression using a human HCC tissue microarray. Correlations were assessed using the two-sided Pearson chi-square test. A P value less than 0.05 was set as the criterion for statistical significance. d Two representative cases from the immunohistochemical staining in (a–c). Scale bar, 50 μm. e A proposed model of RNase1 as a secretory biomarker used to identify treatment options for HCC. In brief, high plasma levels of RNase1 induce immunosuppression by promoting the polarization of TAMs via binding to ALK and trigger ALK/STAT3 signaling, which in turn debilitates antitumor immune responses. ALK inhibitor treatment enhances the efficacy of anti-PD-1 therapy by reprogramming macrophage polarized from pro-tumor phenotype (M2-like) into antitumor phenotype (M1-like), inducing the secretion of T-cell recruiting chemokines, intertumoral accumulation of cytotoxic CD8⁺ T cells, as well as reduction of Tregs. In addition, memory T-cell were enriched and expanded in rechallenged mice. ALK activation and immunosuppressive state triggered by RNase1 could be reversed by ALK inhibitor and anti-PD-1 combination therapy, and RNase1 could serve as a plasma biomarker to identify patients with HCC who may benefit from this therapeutic strategy. Figure was created with BioRender.com.