Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
Immunol Rev. 2024 May;323(1):19-39. doi: 10.1111/imr.13316. Epub 2024 Mar 9.
Natural Killer (NK) cells are a top contender in the development of adoptive cell therapies for cancer due to their diverse antitumor functions and ability to restrict their activation against nonmalignant cells. Despite their success in hematologic malignancies, NK cell-based therapies have been limited in the context of solid tumors. Tumor cells undergo various metabolic adaptations to sustain the immense energy demands that are needed to support their rapid and uncontrolled proliferation. As a result, the tumor microenvironment (TME) is depleted of nutrients needed to fuel immune cell activity and contains several immunosuppressive metabolites that hinder NK cell antitumor functions. Further, we now know that NK cell metabolic status is a main determining factor of their effector functions. Hence, the ability of NK cells to withstand and adapt to these metabolically hostile conditions is imperative for effective and sustained antitumor activity in the TME. With this in mind, we review the consequences of metabolic hostility in the TME on NK cell metabolism and function. We also discuss tumor-like metabolic programs in NK cell induced by STAT3-mediated expansion that adapt NK cells to thrive in the TME. Finally, we examine how other approaches can be applied to enhance NK cell metabolism in tumors.
自然杀伤 (NK) 细胞因其具有多样化的抗肿瘤功能以及能够限制其对非恶性细胞的激活作用，成为癌症过继细胞疗法发展的热门候选者。尽管在血液恶性肿瘤方面取得了成功，但 NK 细胞为基础的疗法在实体肿瘤方面受到了限制。肿瘤细胞经历各种代谢适应，以维持支持其快速和不受控制增殖所需的巨大能量需求。因此，肿瘤微环境 (TME) 中缺乏为免疫细胞活动提供燃料所需的营养物质，并且含有几种抑制 NK 细胞抗肿瘤功能的免疫抑制代谢物。此外，我们现在知道 NK 细胞的代谢状态是决定其效应功能的主要因素。因此，NK 细胞能够承受和适应这些代谢上恶劣的条件对于在 TME 中进行有效和持续的抗肿瘤活性至关重要。考虑到这一点，我们回顾了 TME 中代谢敌意对 NK 细胞代谢和功能的影响。我们还讨论了 STAT3 介导的扩增诱导的 NK 细胞中的肿瘤样代谢程序，这些程序使 NK 细胞能够在 TME 中茁壮成长。最后，我们研究了如何应用其他方法来增强肿瘤中的 NK 细胞代谢。
