Two-photon photosensitizer for specific targeting and induction of tumor pyroptosis to elicit systemic immunity-boosting anti-tumor therapy.

Abstract

Photodynamic therapy (PDT) has garnered increasing attention in cancer treatment due to its precise spatiotemporal selectivity and non-invasive nature. However, several challenges, including the inability of photosensitizers to discriminate between tumor and healthy tissues, as well as the limited tissue penetration depth of light sources, impede its broader application. To surmount these impediments, our research introduces a two-photon photosensitizer (TPSS) that specifically targets tumor overexpressing carbonic anhydrase IX (CA IX), thereby exhibiting exceptional specificity for tumor cells. Under two-photon laser stimulation, TPSS generates a large amount of reactive oxygen species (ROS), inducing cell pyroptosis and subsequently triggering a strong anti-tumor immune response. Additionally, proteomics analysis provides compelling evidence to elucidate the anti-tumor mechanism of TPSS in vivo. Through comprehensive immune assessments, TPSS under two-photon laser irradiation effectively activates both the innate and adaptive immune systems, efficiently suppressing the proliferation of distant metastatic tumors, underscoring its considerable therapeutic potential. Collectively, this study provides a viable strategy to overcome the limitations of PDT, highlighting the prospects of two-photon excitation photosensitizers.