Laser-activated nanoparticles rewire tumor microenvironment enhancing PD-1 blockade and T cell response in cholangiocarcinoma

Background and Aims: Immunotherapy has continued to revolutionize cancer treatment, achieving remarkable progress over the past decade. However, in most solid tumors, its effectiveness is often impaired because of immune resistance driven by the tumor microenvironment (TME). In fibrotic cancers, such as cholangiocarcinoma (CCA), the extracellular matrix (ECM) and cancer-associated fibroblasts (CAFs) form a dense, rigid stroma that hinders immune cell infiltration and promotes immunosuppression. Overcoming these physical and biological barriers is crucial for fully unleashing the potential of immunotherapeutic approaches. Approach and Results: We developed a dual-action strategy combining photothermal therapy (PTT) using gold-decorated iron oxide nanoflowers (GIONFs) and PD-1 immune checkpoint blockade. This approach was evaluated in preclinical models of CCA to assess its impact on ECM remodeling, CAF modulation, immune cell activation, and tumor growth. The combinatorial strategy effectively reduced ECM stiffness, reprogrammed CAF subsets, and enhanced cytotoxic T-cell infiltration. In preclinical CCA models, treated tumors shift from immune-cold to immune-hot states. This combination amplifies antitumor immune responses, decreases immunosuppressive stromal signatures, and improves tumor control. Conclusions: Our findings emphasize the therapeutic potential of combining nanotechnology and immunotherapy to reshape the TME and overcome immunotherapy resistance in fibrotic tumors, such as CCA. Targeting both ECM and immune checkpoints has emerged as a promising and versatile strategy to enhance the efficacy of immunotherapy against desmoplastic cancers.