Dual-Modulation Design to Develop ER-Targeting NIR Pyroptosis Inducers with Type I PDT Efficacy and Amplified Antitumor Immunity

Recently, immunogenic cell death (ICD) activated by phototherapy has attracted increasing attention in anticancer immunotherapy. Pyroptosis, a lysogenic and inflammatory form of cell death distinct from apoptosis, is considered to enhance the ICD process in tumor cells. Endoplasmic reticulum (ER)-targeted pyroptosis induced by phototherapy is reported to promote the release of inflammatory cytokines and DAMPs and amplify ICD response as a result. However, specific and stable tracking of the ER is more difficult than that of other organelles. In this work, we introduce a dual-modulation strategy to regulate the effect of ER-targeting unit p-toluenesulfonamide and twisting conjugation motif on the modification of heptamethine cyanine. A dimer dye (T780T-ER) with twisting structure and four p-toluenesulfonamide molecules is ultimately optimized, which can specifically target ER with good stability and efficient Type I PDT capability. Under PDT/PTT stimulation, T780T-ER activates sufficient pyroptosis and causes the release of inflammatory cytokines and DAMPs. In vivo, promoted ICD response and strengthened antitumor immunity are confirmed against the growth of primary and distant tumors. Summarily, this study highlights the importance of a multiple-modulation strategy in developing ER-targeted photosensitizers and proposes a Type I PDT molecule (T780T-ER) as an ER stress-dependent pyroptosis inducer to enhance antitumor immunotherapy.