Bypassing Ca²⁺ Influx for Antimetastasis Photodynamic Therapy via Robust Nucleus-Targeted Near-Infrared Cyanines

Hypoxia-induced tumor metastasis severely hinders the efficacy of photodynamic therapy (PDT) in cancer treatment. Current strategies predominantly offer palliative suppression of the HIF-1α pathway, emphasizing the urgent need for innovative PDT approaches to prevent metastasis from the outset. Our study revealed that typical PDT triggers an increase in cytoplasmic Ca²⁺ levels, activating HIF-1α, and that reducing Ca²⁺ levels can, in turn, mitigate metastasis. Considering cytoplasm's role in Ca²⁺ storage and regulation, we propose that PDT-induced metastasis can be addressed at its source by precise intracellular localization of photosensitizers (PSs). We developed near-infrared (NIR) cyanine PSs with inherent nucleus targeting capabilities. These PSs effectively inhibit cytoplasmic Ca²⁺ elevation and reduce HIF-1α activity upon irradiation, achieving remarkable antimetastatic effects in 4T1 tumors. Consequently, our findings highlight the pivotal role of Ca²⁺ in PDT-induced metastasis and provide a robust approach for circumventing metastasis from the outset using new nucleus-targeting organic PSs.