肿瘤细胞治疗研究
英文原题：Metabolic reprogramming via LDHB confers resistance to lactate-induced dysfunction and enhanced antitumor activity in hiPSC-Derived NK cells.
我们的研究提供了一种通过重塑代谢途径来增强NK细胞疗法对抗实体瘤的新策略。
自然杀伤（NK）细胞在肿瘤微环境（TME）中通常表现出功能障碍，显著限制了其在抗肿瘤治疗中的疗效。肿瘤细胞表现出增强的糖酵解，导致乳酸（LA）分泌并在 TME 中积累。以人诱导多能干细胞（hiPSC）来源的 NK 细胞（iNKs）为模型，我们证明 LA 诱导显著的 iNK 功能障碍，包括存活率降低、IFN- 分泌受损以及由于线粒体功能严重受损而导致的肿瘤杀伤能力下降。为克服 LA 诱导的功能障碍，我们将乳酸脱氢酶 B（LDHB）表达盒敲入 hiPSCs（LDHB-hiPSCs），使细胞乳酸能够转化为丙酮酸。来源于 LDHB-hiPSCs 的 iNKs（LDHB-iNKs）在很大程度上抵抗了 LA 诱导的功能障碍，在高 LA 肿瘤组织中表现出增强的细胞毒性和改善的存活。重要的是，LDHB-iNKs 在体内对实体瘤形成的抑制作用更强。我们的研究提供了一种通过重塑代谢途径来增强 NK 细胞治疗抗实体瘤的新策略。
Natural Killer (NK) cells generally exhibit dysfunction in tumor microenvironment (TME), significantly limiting their efficacy in antitumor therapy. Tumor cells display enhanced glycolysis, leading to lactic acid (LA) secretion and accumulation in the TME. Using human-induced pluripotent stem cell (hiPSC)-derived NK cells (iNKs) as a model, we demonstrate that LA induces substantial iNK dysfunction, including reduced survival, impaired IFN- secretion, and diminished tumor-killing capacity due to severely compromised mitochondrial function. To overcome LA-induced dysfunction, we knocked in an expression cassette for lactate dehydrogenase B (LDHB) into hiPSCs (LDHB-hiPSCs), enabling conversion of cellular lactate to pyruvate. iNKs derived from LDHB-hiPSCs (LDHB-iNKs) largely resisted LA-induced dysfunction, exhibiting enhanced cytotoxicity and improved survival in high-LA tumor tissues. Importantly, LDHB-iNKs show superior suppression of solid tumor formation in vivo. Our study provides a novel strategy to enhance NK cell therapy against solid tumors by reshaping the metabolic pathways.
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