Yan Ping, Li Fahui, Qin Shuangfeng, Li Zhengbo, Wang Xudong, Xu Guangzhao, Song Weiguo, Sun Wen, Zhong Wenda
School of Pharmacy, Shandong Second Medical University, Weifang 261053, People's Republic of China.
School of Pharmacy, Shandong Second Medical University, Weifang 261053, People's Republic of China.
J Colloid Interface Sci. 2025 Nov 15;698:138085. doi: 10.1016/j.jcis.2025.138085. Epub 2025 Jun 3.
Breast cancer is the most diagnosed cancer type among women worldwide and quite a few will be diagnosed with triple-negative breast cancer (TNBC), which is still a challenge to be treated. Immunotherapy has demonstrated immense therapeutic potential. However, the characteristics of the immunosuppressive tumor microenvironment (ITME) limit the efficacy of immunotherapy in TNBC treatment. Herein, a molecule-electron engineering strategy is employed to optimize the excited state characteristics of endoplasmic reticulum (ER)-targeted photodynamic immunogenic cell death (ICD) stimulators. Beneficial to the large conjugated plane of electron donor, the enhanced spin-orbit coupling (SOC) and promoting intersystem crossing (ISC) boost the 244% higher reactive oxygen species (ROS) production in Cz-IOCy. Due to the superior ROS production and ER-targeted ability, Cz-IOCy induces severe ER stress and arouses the ICD pathway in different breast cancer cells. The amplifying antigen presentation promotes the dendritic cells (DCs) maturation and infiltration of cytotoxic T lymphocytes (CTLs), ultimately overcoming the ITME characteristic and realizing efficient immunotherapy. As a result, the growth of both proximal and distal cancers in TNBC mice models is suppressed, underscoring the efficacy of this molecule-electron engineering strategy for developing photodynamic ICD stimulators and TNBC immunotherapy drugs.
乳腺癌是全球女性中诊断出最多的癌症类型，相当一部分人会被诊断为三阴性乳腺癌（TNBC），其治疗仍然是一项挑战。免疫疗法已显示出巨大的治疗潜力。然而，免疫抑制性肿瘤微环境（ITME）的特征限制了免疫疗法在TNBC治疗中的疗效。在此，采用分子电子工程策略来优化内质网（ER）靶向光动力免疫原性细胞死亡（ICD）刺激剂的激发态特征。得益于电子供体的大共轭平面，增强的自旋轨道耦合（SOC）和促进系间窜越（ISC）使Cz-IOCy中的活性氧（ROS）生成提高了244%。由于卓越的ROS生成能力和ER靶向能力，Cz-IOCy在不同的乳腺癌细胞中诱导严重的内质网应激并激活ICD途径。放大的抗原呈递促进树突状细胞（DCs）成熟和细胞毒性T淋巴细胞（CTLs）浸润，最终克服ITME特征并实现高效免疫疗法。结果，TNBC小鼠模型中近端和远端癌症的生长均受到抑制，突出了这种分子电子工程策略在开发光动力ICD刺激剂和TNBC免疫治疗药物方面的有效性。
