NASIR-HCC JITC 2026

This study analyzed why some patients with unresectable hepatocellular carcinoma benefit from the combination of selective internal radiation therapy (SIRT) and nivolumab. Unlike conventional immunotherapy, treatment response was not determined by the presence of pre-existing T-cell infiltration or inflammatory signatures. Instead, resistance was associated with a fibroblast-rich, fibrotic tumor microenvironment characterized by extracellular matrix remodeling and enrichment of periostin (POSTN)-expressing oncofetal cancer-associated fibroblasts (CAFs). Spatial analyses showed that activated lymphocytes were trapped within these stromal regions, suggesting that a physical stromal barrier limited their antitumor activity. In contrast, responders exhibited enrichment of oxidative phosphorylation pathways. These findings identify stromal composition, rather than baseline immune infiltration, as the main determinant of response to SIRT plus nivolumab and support targeting CAFs and stromal remodeling to improve treatment efficacy.