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<i>-</i>targeting unit <i>p</i>-toluenesulfonamide and twisting conjugation motif on the modification of heptamethine cyanine. A dimer dye (T780T-ER) with twisting structure and four <i>p</i>-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. <i>In vivo</i>, 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.