肿瘤细胞治疗研究
英文原题：Enhancing cancer killing and natural killer cell persistence by targeting NOXA, a predictor of poor patient survival.
Enhancing cancer killing and natural killer cell persistence by targeting NOXA, a predictor of poor patient survival.
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基于自然杀伤（NK）细胞的治疗策略因其强大的靶向和杀伤癌细胞能力，已成为癌症免疫治疗中颇具前景的手段。然而，其临床疗效常受限于NK细胞在体内持久性不足，这阻碍了持续的治疗效果。
本研究旨在通过抑制凋亡来增强NK细胞的存活和功能，从而提升NK细胞介导治疗的长期疗效。通过单因素和多因素Cox比例风险回归分析，我们发现NK细胞中Bcl-2相互作用细胞死亡介质（BCL2L11 [BIM]）和佛波醇-12-肉豆蔻酸酯-13-乙酸酯诱导蛋白1（PMAIP1 [NOXA]）的高表达与多种癌症类型中较差的生存相关。基于潜在的临床相关性，我们采用CRISPR-Cas9技术结合单引导RNA敲除NK细胞中的NOXA。这一修饰在重复实验和患者来源的类器官模型中增强了连续杀伤癌细胞的效力。相比之下，BIM敲除（KO）未带来任何额外益处。
此外，NOXA-KO NK细胞表现出增强的冻存后细胞毒性、更优的代谢适应性以及延长的增殖能力。这些发现凸显了NOXA-KO NK细胞在提升基于NK细胞的癌症治疗疗效方面的潜力。
Natural killer (NK)-cell-based therapeutics have emerged as promising modalities in cancer immunotherapy due to their potent ability to target and kill cancer cells.
However, their clinical efficacy is often constrained by the limited in vivo persistence of NK, which hinders sustained therapeutic effects.
This study aimed to enhance NK cell survival and functionality by inhibiting apoptosis, thereby boosting the long-term efficacy of NK-cell-mediated therapeutics. Through univariate and multivariate Cox proportional hazards regression analyses, we found that the high expression of Bcl-2-interacting mediator of cell death ( BCL2L11 [ BIM ]) and phorbol-12-myristate-13-acetate-induced protein 1 ( PMAIP1 [ NOXA ]) in NK cells is associated with poorer survival across various cancer types.
Based on potential clinical relevance, we employed CRISPR-Cas9 technology with single-guide RNA to knock out NOXA in NK cells. This modification enhanced the serial cancer-killing efficacy in repeated assays and patient-derived organoid models. In contrast, BIM -knockout (KO) did not confer any additional benefits.
Additionally, NOXA -KO NK cells exhibited enhanced post-cryopreservation cytotoxicity, superior metabolic fitness, and extended proliferative capacity.
These findings highlight the potential of NOXA -KO NK cells to advance the efficacy of NK-cell-based cancer therapies.
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