Wang Longqin, Cheng Wenting, Qin Siyuan, Tian Hailong, Liu Guowen, Miao Peng, Huang Canhua, Wang Hao, Jing Jing
Department of Biotherapy, Oxidative Stress Research Center, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
Department of Biotherapy, Oxidative Stress Research Center, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China; Frontiers Medical Center, Tianfu Jincheng Laboratory, Chengdu, 610041, China.
Biomaterials. 2026 Feb;325:123632. doi: 10.1016/j.biomaterials.2025.123632. Epub 2025 Aug 11.
Cancer cells with stemness characteristics effectively escape the recognition and killing of immune-active cells, such as T cells, which has been considered as the root cause of cancer recurrence and metastasis. To sensitize cancer immunotherapy, we have developed salinomycin-repurposed endoplasmic reticulum (ER) stress nanoinducers (DTSS NPs) to synergistically suppress cancer cell stemness. Salinomycin, as a polyether antibiotic demonstrating robust cytotoxicity against tumor stem cell, is co-assembled with thymopentin (TP5) and ER-targeted phototherapeutic agent s-780, and tailored with DSPE-PEG-biotin to obtain DTSS NPs. This nanoplatform not only improves the bioavailability of TP5 and salinomycin, but also ensures controlled drug release and reduces the side effects of therapeutic agents. Moreover, the hyperpyrexia and ROS produced by s-780 further induced ER stress, which downregulates PD-L1 expression and activates the cGAS-STING pathway, while TP5 significantly promotes the proliferation and differentiation of T lymphocytes, resulting in the augment of the anti-tumor immunity. Importantly, salomycin synergistically boosted s-780-mediated ER stress to effectively inhibit the stemness of cancer cells, thereby enhancing the responsiveness of cancer cells to T cells. As expected, DTSS NPs activate systemic immunity and suppress cancer metastasis and recurrence, providing promising solutions for sensitizing cancer immunotherapy by inhibiting cancer cell stemness.
具有干性特征的癌细胞能够有效逃避免疫活性细胞（如T细胞）的识别和杀伤，这被认为是癌症复发和转移的根本原因。为了增强癌症免疫疗法的效果，我们开发了重新利用的盐霉素内质网（ER）应激纳米诱导剂（DTSS NPs），以协同抑制癌细胞的干性。盐霉素作为一种对肿瘤干细胞具有强大细胞毒性的聚醚抗生素，与胸腺五肽（TP5）和内质网靶向光疗剂s-780共同组装，并通过DSPE-PEG-生物素进行修饰，以获得DTSS NPs。这种纳米平台不仅提高了TP5和盐霉素的生物利用度，还确保了药物的可控释放并降低了治疗剂的副作用。此外，s-780产生的高热和活性氧进一步诱导内质网应激，下调PD-L1表达并激活cGAS-STING通路，而TP5显著促进T淋巴细胞的增殖和分化，从而增强抗肿瘤免疫力。重要的是，盐霉素协同增强s-780介导的内质网应激，有效抑制癌细胞的干性，从而增强癌细胞对T细胞的反应性。正如预期的那样，DTSS NPs激活全身免疫，抑制癌症转移和复发，通过抑制癌细胞干性为增强癌症免疫疗法提供了有前景的解决方案。
