Li Guodong, Du Ruoxin, Wang Donghui, Zhang Xiangmei, Wang Lizhuo, Pu Shuangpeng, Li Xiaoju, Wang Shuning, Zhang Juliang, Liu Beichen, Gao Yuan, Zhao Huadong
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an, 710032, P. R. China.
Department of Thyroid, Breast, and Vascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, P. R. China.
Adv Sci (Weinh). 2025 Apr;12(14):e2409835. doi: 10.1002/advs.202409835. Epub 2025 Jan 22.
Leaky and structurally abnormal blood vessels and increased pressure in the tumor interstitium reduce the infiltration of CAR-T cells in solid tumors, including triple-negative breast cancer (TNBC). Furthermore, high burden of tumor cells may cause reduction of infiltrating CAR-T cells and their functional exhaustion. In this study, various effector-to-target (E:T) ratio experiments are established to model the treatment using CAR-T cells in leukemia (high E:T ratio) and solid tumor (low E:T ratio). It is found that the antitumor immune response is decreased in solid tumors with low E:T ratio. Furthermore, single cell sequencing is performed to investigate the functional exhaustion at a low ratio. It is revealed that the inhibition of mitophagy-mediated mitochondrial dysfunction diminished the antitumor efficacy of CAR-T-cell therapy. The mitophagy agonist BC1618 is screened via AI-deep learning and cytokine detection, in vivo and in vitro studies revealed that BC1618 significantly strengthened the antitumor response of CAR-T cells via improving mitophagy. Here, injection hydrogels are engineered for the controlled co-delivery of CAR-T cells and BC1618 that improves the treatment of TNBC. Local delivery of hydrogels creates an inflammatory and mitophagy-enhanced microenvironment at the tumor site, which stimulates the CAR-T cells proliferation, provides antitumor ability persistently, and improves the effect of treatment.
血管渗漏和结构异常以及肿瘤间质压力升高会减少嵌合抗原受体T细胞（CAR-T细胞）在实体瘤（包括三阴性乳腺癌（TNBC））中的浸润。此外，高肿瘤细胞负荷可能导致浸润的CAR-T细胞减少及其功能耗竭。在本研究中，建立了各种效应细胞与靶细胞（E:T）比例实验，以模拟CAR-T细胞在白血病（高E:T比例）和实体瘤（低E:T比例）中的治疗。研究发现，低E:T比例的实体瘤中抗肿瘤免疫反应降低。此外，进行单细胞测序以研究低比例下的功能耗竭。结果表明，抑制线粒体自噬介导的线粒体功能障碍会降低CAR-T细胞疗法的抗肿瘤疗效。通过人工智能深度学习和细胞因子检测筛选出线粒体自噬激动剂BC1618，体内和体外研究表明，BC1618通过改善线粒体自噬显著增强了CAR-T细胞的抗肿瘤反应。在此，设计了注射水凝胶用于CAR-T细胞和BC1618的可控共递送，从而改善TNBC的治疗。水凝胶的局部递送在肿瘤部位创造了一个炎症增强且线粒体自噬增强的微环境，刺激CAR-T细胞增殖，持续提供抗肿瘤能力，并提高治疗效果。
