癌干细胞（CSCs）被认为是癌症复发和转移的罪魁祸首。因此，需要一种治疗方法来消除快速增殖的分化癌细胞和生长缓慢的耐药CSCs。我们使用已建立的卵巢癌细胞系以及从高级耐药卵巢癌患者分离的卵巢癌细胞，证明卵巢CSCs的表面表达NKG2D配体（MICA/B和ULBPs）的水平较低，这是它们逃避自然杀伤（NK）细胞监视的机制。在这里，我们发现，暴露于SN-38后再接受5-FU的卵巢癌（OC）细胞不仅协同杀死了OC细胞，还通过上调NKG2D配体使CSCs易受到NK92细胞攻击。由于这两种药物的全身性给药受到不耐受和不稳定的困扰，我们工程化和分离出一个脂肪来源的干细胞（ASC）克隆，它稳定地表达羧酸酯酶-2和酵母胞嘧啶脱氨酶酶，将伊立替康和5-FC前药转化为SN-38和5-FU细胞毒性药物。ASC和前药与耐药OC细胞的共培养不仅导致耐药OC细胞的死亡，还使它们显著易受到NK92细胞的攻击。本研究为ASC定向靶向化疗与NK92辅助免疫疗法联合消灭耐药性OC细胞提供了原则性证明。 © 2023 Springer Science+Business Media, LLC, part of Springer Nature.

Cancer stem-like cells (CSCs) are believed to be responsible for cancer recurrence and metastasis. Therefore, a therapeutic approach is needed to eliminate both rapidly proliferating differentiated cancer cells and slow-growing drug-resistant CSCs. Using established ovarian cancer cells lines as well as ovarian cancer cells isolated from a patient with high-grade drug-resistant ovarian carcinoma, we demonstrate that ovarian CSCs consistently express lower levels of NKG2D ligands (MICA/B and ULBPs) on their surfaces, a mechanism by which they evade natural killer (NK) cells' surveillance. Here, we discovered that exposure of ovarian cancer (OC) cells to SN-38 followed by 5-FU not only acts synergistically to kill the OC cells, but also makes the CSCs vulnerable to NK92 cells through upregulation of NKG2D ligands. Since systemic administration of these two drugs is marred by intolerance and instability, we engineered and isolated an adipose-derived stem cell (ASC) clone, which stably expresses carboxylesterase-2 and yeast cytosine deaminase enzymes to convert irinotecan and 5-FC prodrugs into SN-38 and 5-FU cytotoxic drugs, respectively. Co-incubation of ASCs and prodrugs with drug-resistant OC cells not only led to the death of the drug-resistant OC cells but also made them significantly vulnerable to NK92 cells. This study provides proof of principle for a combined ASC-directed targeted chemotherapy with NK92-assisted immunotherapy to eradicate drug-resistant OC cells.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.