A photoactivated nanoreactor cascade amplifies immunogenic endoplasmic reticulum stress for hepatocellular carcinoma immunotherapy.

Immunotherapy has emerged as a promising strategy for hepatocellular carcinoma (HCC), its effectiveness is significantly limited by insufficient immunogenic cell death (ICD). Here, we developed a photoactivated nanoreactor (ADDT) by integrating a trans-vaccenic acid (TVA)-coated degradable dendritic mesoporous silica nanoparticle (DMSN) core co-loaded with Au NPs and doxorubicin (DOX) to induce cascade-mediated endoplasmic reticulum (ER) stress in HCC therapy. Near-infrared irradiation melted the TVA through the photothermal conversion of aggregated Au NPs, triggering GSH-responsive DMSN degradation. The released Au NPs deplete glucose, and together with mild photothermal therapy and DOX chemotherapy, significantly increase ROS production and amplify ER stress. This cascade culminates in a potent ICD effect. The released tumor-specific antigens facilitate dendritic cell maturation, while TVA further enhances tumor infiltration by CD8+ T cells. These synergistic actions effectively suppress both primary tumors and pulmonary metastasis. This study provides a strategy to overcome the limitations of tumor immunogenicity and activate a potent antitumor immune response.