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Restoring both adaptive and innate immunity represents a promising therapeutic strategy. In this study, a novel photodynamic therapy (PDT) platform is developed that simultaneously activates both adaptive immunity through T cells and innate immunity through natural killer (NK) cells, thereby fostering a synergistic anti\u2010tumor immune response in MM. A series of aggregation\u2010induced emission luminogen (AIEgen)\u2010based photosensitizers is synthesized and compared, identifying a dual\u2010acceptor molecular design with superior PDT efficacy. The high\u2010performance AIEgen is formulated into nanoparticles and functionalized with B\u2010cell maturation antigen monoclonal antibodies for precise MM targeting. Upon photoactivation, the nanoagent triggers immunogenic cell death, dendritic cell activation, and T\u2010cell priming. Simultaneously, it induces DNA damage in MM cells, upregulating MICA\/B expression via the ATM\/SMAD1 pathway to activate NK cells through NKG2D receptor engagement. In vivo studies using an NSG mouse model demonstrate robust activation of patient\u2010derived T and NK cells, leading to potent anti\u2010MM effects. This work presents a dual\u2010pronged immunotherapeutic strategy to overcome immune suppression in MM, offering a synergistic approach to harness both adaptive and innate immunity for enhanced cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202518663","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T08:00:02Z","timestamp":1764403202000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Harnessing Targeted Photodynamic Therapy to Synergistically Activate T Cell and NK Cell Responses in Multiple Myeloma"],"prefix":"10.1002","volume":"38","author":[{"given":"Zhaoyun","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Hematology, Tianjin Medical University General Hospital Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control Tianjin Institute of Hematology State Key Laboratory of Experimental Hematology  Tianjin 300052 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