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Although chlorin\u2010based sensitizers have achieved clinical success in phototherapy, their translation to SDT has been impeded by inadequate ultrasound (US)\u2010triggered reactive oxygen species (ROS) generation, leading to suboptimal immunogenic cell death (ICD) and compromised antitumor immunity. To address this, we designed two organic sonosensitizers based on the natural product\u2010derived scaffold, Chenghai pyropheophorbide\u2010a (CHPpa). CHPpa\u2010er was constructed by appending a\n                    <jats:italic>p<\/jats:italic>\n                    \u2010toluenesulfonamide group for specific endoplasmic reticulum (ER) targeting. Its analogue, CHPpa\u2010er\u2010Asp, was additionally functionalized with aspartic acid to modulate molecular polarity. Remarkably, despite differing by only one pharmacophore, the two compounds exhibited profoundly distinct profiles in target protein (K\n                    <jats:sub>ATP<\/jats:sub>\n                    channel) engagement and intracellular trafficking, highlighting the critical impact of rational molecular design. As the lead candidate, CHPpa\u2010er elicited precise, intraluminal ROS bursts under US, inducing severe ER stress and robust ICD. In two preclinical tumor models, CHPpa\u2010er\u2010mediated SDT effectively suppressed both primary tumor growth and metastasis by provoking potent systemic antitumor immunity. This work introduced a unimolecular sonosensitizer strategy that transformed SDT from a localized modality into a systemic intervention, offering a translatable platform for comprehensive cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/anie.8129050","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:28:10Z","timestamp":1788258490000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sono\u2010Triggered In Situ Vaccine via a Chlorin\u2010Based Small Molecule Sensitizer for Systemic Cancer Therapy"],"prefix":"10.1002","volume":"65","author":[{"given":"Jinrong","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Fine Chemicals Department of Pharmaceutical Engineering School of Chemical Engineering Dalian University of Technology  Dalian China"},{"name":"State Key Laboratory of Fine Chemicals Frontiers Science Center For Smart Materials 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