H Q Liu, Qiao He, Dong‐Xu Wang, J T Liu, J T Liu, Ying Qu, Daolin Zhang, Pengfei Sun, Hui Li, Shengxuan Peng, Ruizhe Li, Zhaoru Dong, Jianhua Zou, J T Liu, J T Liu, TT Li
Hepatocellular carcinoma (HCC) shows limited responsiveness to immune checkpoint inhibitors (ICIs), largely because many tumors remain poorly inflamed and refractory to effective antitumour immunity. Here, we identify Z-DNA-binding protein 1 (ZBP1) as an immune-associated determinant of therapeutic responsiveness in HCC and explore its potential as a target for radio-immunotherapy sensitization. Integrative analysis of necroptosis-related genes and immunotherapy-response datasets revealed that high ZBP1 expression was associated with favourable survival, enhanced antigen-presentation signatures, increased immune-cell infiltration, and improved immunotherapy benefit. Functionally, basal ZBP1 expression alone had limited effects on tumor-cell behavior, whereas pharmacological activation of ZBP1 markedly enhanced therapeutic responsiveness. Mechanistically, ZBP1 activation promoted necroptosis-associated signaling and amplified IFN and STING-related innate immune activation. Radiotherapy further upregulated ZBP1, providing a mechanistic basis for combination treatment. To enable tumor-directed delivery, we developed a glypican-3 (GPC3)-targeted liposomal nanoplatform co-loaded with the ZBP1 agonist CBL0137 and gold nanoparticles (CBL-Au@Lip). CBL-Au@Lip exhibited stable physicochemical properties, acceptable biosafety, and enhanced tumor-associated accumulation. In vitro, CBL-Au@Lip cooperated with radiotherapy to suppress malignant phenotypes and strengthen immune-related signaling. In orthotopic HCC models, triple therapy comprising radiotherapy, anti-PD-L1 antibody (aPD-L1), and CBL-Au@Lip achieved superior tumor control, increased intratumoral T-cell infiltration and cytotoxic activation, and induced durable antitumour immune memory. Importantly, this therapeutic benefit was retained in a fibrosis-associated HCC model, although no obvious antifibrotic effect was observed. Together, these findings identify targeted ZBP1 activation as a promising strategy to enhance radio-immunotherapy and support further translational development of CBL-Au@Lip-based combination therapy in HCC.