CTSC Confers Radioresistance in Hepatocellular Carcinoma by Regulating Myeloid‐Derived Suppressor Cells

ABSTRACT Radiotherapy is an important therapeutic modality for advanced hepatocellular carcinoma (HCC), but the limited understanding of radioresistance mechanisms in HCC has hindered its further clinical development. This work aimed to clarify the essential role of Cathepsin C (CTSC) in regulating radioresistance in HCC. The expression of CTSC in HCC tissues was analysed using real‐time PCR (RT‐PCR) and immunohistochemistry. The role of CTSC in radiotherapy resistance of HCC was investigated through in vitro experiments, in vivo studies (subcutaneous and orthotopic liver tumour models) and clinical data analysis. Additionally, in vivo experiments were conducted to evaluate the effect of blocking the CTSC signalling pathway on reversing radiotherapy resistance in HCC. CTSC expression was significantly higher in HCC tissues than in adjacent non‐tumour tissues. Correlation analysis showed that positive CTSC expression was positively associated with aggressive clinicopathological features, including increased tumour number, large tumour size, absence of tumour encapsulation, microvascular invasion and advanced TNM stage. Survival analysis further revealed that CTSC overexpression was linked to poorer overall survival (OS) and progression‐free survival (PFS) in HCC patients. In vitro experiments demonstrated that CTSC overexpression increased the clonogenic survival rate of Huh7 cells after ionising radiation (IR) and reduced the apoptosis rate. In both subcutaneous and orthotopic liver tumour models, upregulated CTSC expression significantly decreased radiotherapy sensitivity. Clinically, CTSC overexpression was significantly associated with a poor response to radiotherapy. Mechanistically, CTSC promoted the infiltration of myeloid‐derived suppressor cells (MDSCs) while reducing CD8 + T cell infiltration by upregulating CXCL1 expression. Importantly, the combination of the CTSC inhibitor AZD7986 with radiotherapy significantly improved radiotherapy sensitivity in HCC models. CTSC contributes to radiotherapy resistance in HCC by recruiting MDSCs. The synergistic application of a CTSC inhibitor with radiotherapy represents an effective combinational treatment strategy for CTSC‐positive HCC.