Combination strategy of photothermal therapy and targeted IFN-β mutein priming elicits a durable abscopal effect

Metastatic tumors remain difficult to cure due to frequent dissemination and recurrence. While photothermal therapy (PTT) can trigger abscopal effects, PTT monotherapy often fails to sustain systemic immunity. Here, we investigated a tripartite strategy combining PTT, a tumor-targeted type I interferon immunocytokine, and immune checkpoint blockade. Using an engineered claudin-3–targeted IFN-β mutein (CLDN3–IFN-βm) in human IFNAR1/2 knock-in mice, we found that combining PTT with CLDN3–IFN-βm synergistically reprogrammed the tumor microenvironment. This combination expanded activated dendritic cells in tumor-draining lymph nodes and enhanced CD8⁺ T cell infiltration into untreated distant tumors, thereby establishing durable immune memory. Crucially, this robust activation induced adaptive resistance through upregulation of the PD-1/PD-L1 axis. Accordingly, adding PD-1 blockade led to marked tumor regression and sustained systemic antitumor immunity, offering a potential curative strategy for metastatic solid tumors.