Harnessing Targeted Photodynamic Therapy to Synergistically Activate T Cell and NK Cell Responses in Multiple Myeloma

Abstract

Abstract Multiple myeloma (MM) remains an incurable malignancy, with immune suppression in the bone marrow microenvironment playing a critical role in disease progression and relapse. 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‐tumor immune response in MM. A series of aggregation‐induced emission luminogen (AIEgen)‐based photosensitizers is synthesized and compared, identifying a dual‐acceptor molecular design with superior PDT efficacy. The high‐performance AIEgen is formulated into nanoparticles and functionalized with B‐cell maturation antigen monoclonal antibodies for precise MM targeting. Upon photoactivation, the nanoagent triggers immunogenic cell death, dendritic cell activation, and T‐cell 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‐derived T and NK cells, leading to potent anti‐MM effects. This work presents a dual‐pronged immunotherapeutic strategy to overcome immune suppression in MM, offering a synergistic approach to harness both adaptive and innate immunity for enhanced cancer immunotherapy.