肿瘤细胞治疗研究
英文原题：Cryo-trojan mesenchymal stem cells as non-living tumor-homing supercarriers for enhanced drug delivery and immune activation in prostate cancer.
CT-MTX 是一种新型、非增殖性药物递送平台，它将 MSC 的肿瘤归巢能力与增强的安全性及控释特性相结合，可诱导前列腺癌和其他免疫学“冷”肿瘤中的免疫原性细胞死亡（ICD），以改善免疫浸润。
背景：前列腺癌仍是癌症相关死亡的主要原因，常规疗法受全身毒性和肿瘤靶向能力不足限制。开发可提高治疗特异性、同时最大限度减少脱靶效应的创新药物递送系统至关重要。材料与方法：研究者将冷冻特洛伊木马人脐带间充质干细胞（CT-MSC）设计为非活体、具有肿瘤归巢能力的米托蒽醌（MTX）载体，称为 CT-MTX。冷冻处理保留了细胞结构完整性及趋化因子受体 CXCR4/CCR2，维持肿瘤靶向能力，同时消除了增殖风险。综合评价包括药物负载和释放动力学、体外肿瘤抑制、免疫原性细胞死亡（ICD）诱导，以及前列腺癌模型中的体内疗效和安全性。结果：CT-MTX 药物负载能力更强（116.38 μg/10⁶ 个细胞），并具有 pH 敏感性释放特征（pH 5.5 时释放 74.10%）；其稳定性和肿瘤特异性递送能力优于外泌体、脂质体和活 MSC。与靶向性较弱的脂质体和存在生物相容性顾虑的纳米材料相比，CT-MTX 利用 MSC 来源的组织趋向性，同时避免致瘤风险。体外实验中，CT-MTX 抑制肿瘤增殖（MTX 摄取率 84.83%）、抑制迁移（残余迁移 4.42%）并诱导细胞凋亡（晚期凋亡 43.23%）。机制上，CT-MTX 通过释放病原体相关分子模式（PAMP）触发 ICD，激活 CD8⁺ T 细胞并抑制免疫抑制性 Treg。体内 CT-MTX 选择性聚集于肿瘤，使肿瘤生长减少 87.88%，生存率延长（93.30%，对照组 66.70%），且全身毒性可忽略。蛋白质组学发现包括 NK 细胞细胞毒性在内的免疫通路富集，验证了该平台兼具直接杀伤肿瘤和免疫激活作用。结论：CT-MTX 是一种新型非增殖性药物递送平台，结合 MSC 的肿瘤归巢能力、较高安全性和可控释放，可诱导 ICD，用于前列腺癌及其他免疫学“冷”肿瘤，促进免疫浸润。
BACKGROUND: Prostate cancer remains a leading cause of cancer-related mortality, with conventional therapies limited by systemic toxicity and poor tumor targeting. Developing innovative drug delivery systems that enhance therapeutic specificity while minimizing off-target effects is critical. MATERIALS AND METHODS: We engineered cryo-trojan human umbilical cord mesenchymal stem cells (CT-MSCs) as non-living, tumor-homing carriers for mitoxantrone (MTX), termed CT-MTX. Cryo-treatment preserved structural integrity and chemokine receptors (CXCR4/CCR2) for tumor targeting while eliminating proliferative risks. Comprehensive evaluations included drug loading/release kinetics, in vitro tumor suppression, immunogenic cell death (ICD) induction, and in vivo efficacy/safety in prostate cancer models. RESULTS: CT-MTX demonstrated superior drug loading (116.38 g/10 6 cells) and pH-sensitive release (74.10 % at pH 5.5), outperforming exosomes, liposomes, and living MSCs in stability and tumor-specific drug delivery. Compared to liposomes (low targeting) and nanomaterials (biocompatibility concerns), CT-MTX leveraged MSC-derived tropism without tumorigenic risks. In vitro, CT-MTX inhibited tumor proliferation (84.83 % MTX uptake), migration (4.42 % residual migration), and induced apoptosis (43.23 % late apoptosis). Mechanistically, CT-MTX triggered ICD via PAMPs release, activating CD8 + T cells and suppressing immunosuppressive Treg. In vivo, CT-MTX selectively accumulated in tumors, reducing growth by 87.88 % and extending survival (93.30 % vs. 66.70 % in controls) with negligible systemic toxicity. Proteomics revealed enriched immune pathways like NK cell cytotoxicity, validating its dual role in direct tumor killing and immune activation. CONCLUSION: CT-MTX represents a novel, non-proliferative drug delivery platform that combines the tumor-homing capacity of MSCs with enhanced safety and controlled release, inducing ICDs for prostate cancer and other immunologically "cold" tumors to improve immune infiltration.
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