肿瘤细胞治疗研究
英文原题：Nicotinamide mononucleotide potentiates the anti-tumor efficacy of CAR-NK cell therapy targeting MSLN in ovarian cancer.
通过系统评估，我们发现补充 NMN 显著增强了 CAR-NK 细胞的活化标志物表达（CD69、NKG2D）、脱颗粒能力（CD107a⁺ 增加 21.7±1.1%）和细胞因子产生（IFN-γ 升高 1.3 倍）。
靶向间皮素（MSLN）的嵌合抗原受体工程化 NK 细胞（MSLN CAR-NK）已成为治疗多种恶性肿瘤的有前景的现货型免疫疗法，但临床转化仍受细胞毒效力不足和持续性有限的制约。本研究评估烟酰胺单核苷酸（NMN）——一种已知可增强免疫细胞功能的代谢调节剂——能否提高 MSLN CAR-NK 细胞治疗卵巢癌（OC）的效果。系统评估发现，补充 NMN 显著提高 CAR-NK 细胞活化标志物（CD69、NKG2D）的表达和脱颗粒能力（CD107a 增加21.7±1.1%），并使细胞因子产生增加（IFN-γ升高1.3倍）。此外，NMN 处理增强了 MSLN CAR-NK 细胞对 MSLN 阳性靶细胞的细胞毒作用；在效应细胞与靶细胞比为25:1时，特异性裂解率达到32.8±1.4%，同时与对照组相比细胞凋亡减少。转录组分析提示，NMN 调节 PLC-γ 磷酸化级联反应及线粒体氧化还原稳态。值得注意的是，NMN 有效抵消了肿瘤微环境诱导的线粒体活性氧（ROS）蓄积；在 OC 条件培养基中，ROS 降低25.1±0.8%。在 OVCAR8-MSLN 异种移植模型中，回输经 NMN 预处理的 CAR-NK 细胞较对照实现更好的肿瘤控制、增殖（Ki67）和血管生成（CD31）减少，以及瘤内 CAR-NK 浸润增加。上述结果表明，NMN 可通过增强效应功能代谢状态并保护细胞免受微环境氧化抑制这两种机制，提高 CAR-NK 细胞疗效；这为改进卵巢癌 CAR-NK 治疗提供了具有转化潜力的策略。
Chimeric antigen receptor-engineered NK cells targeting mesothelin (MSLN CAR-NK) have emerged as promising off-the-shelf immunotherapeutics for multiple malignancies. However, their clinical translation remains constrained by inefficient cytotoxic potency and limited persistence. This study investigated the therapeutic potential of nicotinamide mononucleotide (NMN), a metabolic modulator known to enhance immune cell functionality, in augmenting MSLN CAR-NK cell efficacy against ovarian cancer (OC). Through systematic evaluation, we found that NMN supplementation significantly enhanced CAR-NK cell activation marker expression (CD69, NKG2D), degranulation capacity (CD107a + increased by 21.7 1.1%), and cytokine production (IFN- elevated 1.3-fold). In addition, NMN treatment potentiated MSLN CAR-NK cell-mediated cytotoxicity against MSLN + target cells, achieving 32.8 1.4% specific lysis at an effector-to-target ratio of 25:1, while concurrently reducing cellular apoptosis compared with controls. Mechanistic interrogation via transcriptomic profiling revealed NMN-mediated modulation of PLC- phosphorylation cascades and mitochondrial redox homeostasis. Notably, NMN effectively counteracted tumor microenvironment-induced mitochondrial ROS accumulation (reduced by 25.1 0.8% in OC-conditioned medium). Critically, in an OVCAR8-MSLN xenograft model, adoptive transfer of NMN-preconditioned CAR-NK cells led to superior tumor control, reduced proliferation (Ki67), diminished angiogenesis (CD31), and enhanced intratumoral CAR-NK infiltration compared with controls. These findings establish NMN as a clinically relevant adjuvant that augments CAR-NK cell efficacy through dual mechanisms: metabolic enhancement of effector functions and protection against microenvironmental oxidative suppression, thereby offering a translatable strategy to improve CAR-NK therapy for ovarian cancer.
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