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

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.