华中师范大学孙耀团队报道了用超分子免疫原性细胞死亡诱导剂增强癌症治疗——一种溶体靶向NIR-光活化钌（II）金属环。相关研究成果于2024年3月21日发表在《美国化学会杂志》。

尽管免疫原性细胞死亡（ICD）在抗癌治疗领域引起了极大的关注，但在深层肿瘤中以最小的副作用有效刺激强烈的免疫反应仍然具有挑战性。

该文中，研究人员介绍了一种新型的自组装近红外光活化钌（II）金属环Ru1105（λ_em=1105nm），作为Ru（II）超分子ICD诱导剂的第一个例子。Ru1105通过多种调节方法协同增强免疫调节反应，减少深层肿瘤的不良反应，包括近红外光激发、增加活性氧（ROS）的产生、肿瘤细胞的选择性靶向、精确的细胞器定位和提高肿瘤穿透/滞留能力。

具体而言，Ru1105表现出优异的深度活化ROS产生（～1cm）、强的扩散阻力和抗ROS猝灭。此外，Ru1105在癌症细胞和多细胞肿瘤球体中的细胞摄取和ROS产生方面表现出有希望的结果。重要的是，与传统抗癌药物奥沙利铂（300μM）相比，Ru1105在超低剂量（10μM）下诱导更有效的ICD。体内实验进一步证实了Ru1105作为ICD诱导剂的效力，引发CD8⁺T细胞反应并以最小的不良反应消耗Foxp3⁺T细胞。

该研究为免疫疗法中安全且特别有效的金属基ICD药物的设计奠定了基础。

附：英文原文

Title: Augmenting Cancer Therapy with a Supramolecular Immunogenic Cell Death Inducer: A Lysosome-Targeted NIR-Light-Activated Ruthenium(II) Metallacycle

Author: Le Tu, Chonglu Li, Qihang Ding, Amit Sharma, Meiqin Li, Junrong Li, Jong Seung Kim, Yao Sun

Issue&Volume: March 21, 2024

Abstract: Though immunogenic cell death (ICD) has garnered significant attention in the realm of anticancer therapies, effectively stimulating strong immune responses with minimal side effects in deep-seated tumors remains challenging. Herein, we introduce a novel self-assembled near-infrared-light-activated ruthenium(II) metallacycle, Ru1105 (λem = 1105 nm), as a first example of a Ru(II) supramolecular ICD inducer. Ru1105 synergistically potentiates immunomodulatory responses and reduces adverse effects in deep-seated tumors through multiple regulated approaches, including NIR-light excitation, increased reactive oxygen species (ROS) generation, selective targeting of tumor cells, precision organelle localization, and improved tumor penetration/retention capabilities. Specifically, Ru1105 demonstrates excellent depth-activated ROS production (～1 cm), strong resistance to diffusion, and anti-ROS quenching. Moreover, Ru1105 exhibits promising results in cellular uptake and ROS generation in cancer cells and multicellular tumor spheroids. Importantly, Ru1105 induces more efficient ICD in an ultralow dose (10 μM) compared to the conventional anticancer agent, oxaliplatin (300 μM). In vivo experiments further confirm Ru1105’s potency as an ICD inducer, eliciting CD8+ T cell responses and depleting Foxp3+ T cells with minimal adverse effects. Our research lays the foundation for the design of secure and exceptionally potent metal-based ICD agents in immunotherapy.

DOI: 10.1021/jacs.3c13224

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.3c13224