[摘 要] 胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）具有高度侵袭性、早期诊断率低且对全身治疗总体反应有限， 其致密纤维化基质、异常血管与免疫抑制性肿瘤微环境共同导致药物渗透不足与免疫“冷肿瘤”特征，是疗效受限的重要原因。 间充质基质细胞（mesenchymal stromal cell, MSC）具有趋炎性迁移、免疫调控与旁分泌效应，可作为“活体递送载体”将细胞因子、 化疗药物、溶瘤病毒及自杀基因等定向输送至肿瘤区域，从而为突破基质屏障与重塑微环境提供策略空间（摘要图）。然而，MSC在肿瘤情境下存在显著可塑性与“双刃剑效应”，可能被肿瘤微环境再教育而表现出免疫抑制、促血管生成、促纤维化、促侵袭及促耐药等不良作用；同时其体内分布与载荷释放缺乏可量化与可控证据链，制备工艺与功能质控标准不统一，构成转化瓶颈。本文重点评述MSC与PDAC微环境相互作用机制及工程化MSC递送治疗性蛋白、药物、溶瘤病毒与自杀基因等研究进展，并探讨 · · 589 [[PAGE_INDEX=2 FILE=202606最新正文_1-30.pdf]] 中国肿瘤生物治疗杂志, 2026, 33(6)安全性、有效性评价与质量控制挑战。发展具有微环境响应释放与安全开关的可编程MSC平台，建立面向肿瘤治疗的功能评价或放行体系，并推进MSC衍生细胞外囊泡等无细胞策略，或将更有利于提升可重复性与降低体内持久性相关风险。 MSC通过直接培养、病毒感染、基因工程等方式负载抗癌药物，如肿瘤坏死因子-α（tumor necrosis factor-α, TNF-α）、肿瘤坏死因子相关凋亡诱导配体（tumor necrosis factor-related apoptosis-inducing ligand, TRAIL）、溶瘤腺病毒、紫杉醇纳米颗粒、吉西他滨、单纯疱疹病毒胸苷激酶等，并凭借其肿瘤归巢特性靶向递送至PDAC组织。 摘要图MSC负载治疗性载荷治疗PDAC示意图

[Abstract] Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive, often diagnosed at late stages, and generally shows limited response to systemic therapies. The dense fibrotic stroma, abnormal vasculature, and immunosuppressive tumor microenvironment collectively impair drug penetration and contribute to the "cold tumor" phenotype, significantly limiting therapeutic efficacy. Mesenchymal stromal cells (MSCs), known for their inflammatory-directed migration, immune modulation, and paracrine effects, can serve as living delivery vehicles to selectively deliver cytokines, chemotherapeutic agents, oncolytic viruses, and suicide genes to tumor sites, offering promising strategies to overcome stromal barriers and reshape the tumor microenvironment. However, MSCs exhibit significant plasticity in the tumor context, displaying a "double-edged sword" effect, potentially being reprogrammed by the tumor microenvironment to exert immunosuppressive, pro-angiogenic, pro-fibrotic, pro-invasive, and drug-resistance-supporting activities. Moreover, the in vivo distribution and payload release of MSCs lack quantifiable and controllable evidence, while inconsistent manufacturing processes and functional quality control standards hinder clinical translation. This review focuses on the mechanisms underlying MSC-tumor microenvironment interactions and recent advances in engineered MSC-based delivery of therapeutic proteins, drugs, oncolytic viruses, and suicide genes, with particular emphasis on challenges related to safety, efficacy evaluation, and quality control. Developing programmable MSC platforms with microenvironment-responsive release and safety switches, establishing functional evaluation or release criteria for tumor therapy, and advancing cell-free approaches such as MSC-derived extracellular vesicles may enhance reproducibility and reduce risks associated with long-term persistence in vivo.

[基金项目] 中国博士后科学基金（GZC20242279）；上海市自然科学基金（25ZR1404012）