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Here, we report the first example of a light-driven, carrier-free, plasma membrane-to-nucleus cascade-targeting photosensitizer (PMNu-4-NI) that operates through a single small molecule. Designed with a hydrophobic, planar naphthalimide unit and a dicationic triphenylamine pyridinium core, PMNu-4-NI initially anchors in the plasma membrane. Upon light irradiation, localized ROS generation disrupts membrane integrity, triggering pyroptosis via the caspase-1\/GSDMD pathway, while simultaneously releasing the molecule from the membrane. The liberated photosensitizer then translocates into the nucleus, where the naphthalimide moiety intercalates into DNA and activates the cGAS-STING pathway. This dual, time-resolved action couples membrane-initiated pyroptosis with nuclear-initiated STING activation, producing a robust immunogenic cell death response. In a murine 4T1 breast tumor model, PMNu-4-NI achieves potent antitumor efficacy with negligible systemic toxicity. Furthermore, in vivo immune profiling reveals enhanced CD8+ T cell infiltration, a significant abscopal effect, and effective suppression of lung metastasis, collectively confirming systemic antitumor immune activation. This work establishes a design paradigm for photodynamic immunotherapy and a generalizable platform for next-generation photosensitizers with programmable spatiotemporal dynamics.<\/jats:p>","DOI":"10.1021\/acsami.6c14820","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T07:01:17Z","timestamp":1789023677000},"page":"50604-50616","source":"Crossref","is-referenced-by-count":0,"title":["Light-Driven Plasma Membrane-to-Nucleus Cascade Targeting Achieves Concurrent Pyroptosis and STING Activation"],"prefix":"10.1021","volume":"18","author":[{"given":"Xingxing","family":"Ma","sequence":"first","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Qi","family":"Li","sequence":"additional","affiliation":[{"name":"Shandong University , , ,","place":["Jinan, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitao","family":"Song","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yile","family":"Zhao","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atikaimu","family":"Aili","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0835-8803","authenticated-orcid":true,"given":"Kang-Nan","family":"Wang","sequence":"additional","affiliation":[{"name":"Shandong University , , ,","place":["Jinan, China, 250100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiejun","family":"Mi","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5641-3539","authenticated-orcid":true,"given":"Yanrong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Northwest A&F University , , , ,","place":["Yangling, Shaanxi, China, 712100"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"issue":"6","key":"2026100820081137500_cit1","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/s41573-024-00920-9","article-title":"Targeting Immunogenic Cell Stress and Death for Cancer Therapy","volume":"23","author":"Galluzzi","year":"2024","journal-title":"Nat. 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