Activated gold-decorated nanoparticles enhance PD-1 blockade and promote cytotoxic T cell anti-tumor responses in cholangiocarcinoma

Immunotherapy has revolutionized cancer treatment over the past decade. However, in most solid tumors, its effectiveness is often impaired owing to immune-resistance mediated through the tumor microenvironment (TME). In fibrotic cancers such as cholangiocarcinoma (CCA), the extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) create a dense, rigid stroma that hinders immune cell infiltration and fosters immunosuppression. Overcoming these physical and biological barriers is critical to fully unleash the potential of immunotherapeutic approaches. Here, the combination of photothermal therapy (PTT) with gold-iron oxide nanoflowers (GIONFs) effectively reshapes the TME by reducing ECM stiffness and facilitating immune cell infiltration. The GIONF-mediated TME mechanical reprogramming in combination with PD-1 immune checkpoint blockade leads to T-cell activation and reduces the immunosuppressive CAF subset. In preclinical models, this combination approach significantly supported anti-tumor immune responses and improved tumor control. Our findings emphasize the therapeutic potential of reshaping the TME to overcome immunotherapy resistance in fibrotic tumors like CCA. Targeting both the ECM and immune checkpoints may therefore represent a promising strategy to improve the efficacy of immunotherapy against desmoplastic cancers.