肿瘤细胞治疗研究
英文原题：Harnessing Targeted Photodynamic Therapy to Synergistically Activate T Cell and NK Cell Responses in Multiple Myeloma.
多发性骨髓瘤（MM）仍是一种无法治愈的恶性肿瘤，骨髓微环境中的免疫抑制在疾病进展和复发中起着关键作用。
多发性骨髓瘤（MM）仍是一种无法治愈的恶性肿瘤，骨髓微环境中的免疫抑制在疾病进展与复发中发挥着关键作用。同时恢复适应性免疫与固有免疫是一种有前景的治疗策略。在本研究中，开发了一种新型光动力治疗（PDT）平台，该平台可同时通过 T 细胞激活适应性免疫、通过自然杀伤（NK）细胞激活固有免疫，从而在 MM 中促成协同抗肿瘤免疫应答。合成并比较了一系列基于聚集诱导发光发光原（AIEgen）的光敏剂，鉴定出一种具有更优 PDT 疗效的双受体分子设计。将高性能 AIEgen 配制成纳米颗粒，并用 B 细胞成熟抗原单克隆抗体进行功能化修饰，以实现对 MM 的精准靶向。光激活后，该纳米制剂触发免疫原性细胞死亡、树突状细胞活化及 T 细胞致敏。同时，它诱导 MM 细胞发生 DNA 损伤，经 ATM/SMAD1 通路上调 MICA/B 表达，从而通过 NKG2D 受体结合激活 NK 细胞。使用 NSG 小鼠模型进行的体内研究显示，患者来源的 T 细胞和 NK 细胞被强效激活，产生强效抗 MM 效应。本工作提出了一种双管齐下的免疫治疗策略，以克服 MM 中的免疫抑制，为同时利用适应性免疫与固有免疫以增强肿瘤免疫治疗提供了一种协同途径。
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.
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