A Multimodal Nanoplatform Integrating Photodynamic Therapy and Wnt/β-Catenin Inhibition Reprograms the Tumor Microenvironment to Potentiate Immune Checkpoint Therapy in Triple-Negative Breast Cancer

The immunosuppressive tumor microenvironment (TME) poses a critical barrier to the efficacy of immune checkpoint inhibitors in triple-negative breast Cancer (TNBC). Here, we report a self-assembled polymeric nanoplatform coloading the Photosensitizer verteporfin and the Wnt/β-catenin Inhibitor XAV-939. This dual-functional system enhanced cellular uptake and potentiated photodynamic therapy (PDT)-induced immunogenic cell death, while simultaneously downregulating β-catenin signaling to reverse immunosuppression. In vivo, the nanoplatform substantially improved therapeutic outcomes, converting "cold" tumors into immune-responsive phenotypes characterized by augmented dendritic cell maturation, increased cytotoxic T cell infiltration, reduced regulatory T cell abundance, and enhanced proinflammatory cytokine release. Combined with PD-L1 blockade, this strategy synergistically activated systemic antitumor immunity, resulting in primary tumor regression, metastasis reduction, and systemic abscopal effects against distal tumors. These results highlight the promise of targeted TME reprogramming as a strategy to overcome TNBC's recalcitrance to immunotherapy.

Wnt/β-catenin signaling pathway; immune checkpoint inhibitors; photodynamic therapy; triple-negative breast cancer; tumor microenvironment.