Targeting lactate metabolism for cancer immunotherapy - a matter of precision
Abstract
Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.
摘要
免疫检查点抑制剂和过继性T细胞疗法已经成为抗癌治疗的有价值的补充方式。这些治疗方法极大地增加了无癌生存的患者数量。然而，在一些患者和肿瘤实体中，癌症免疫治疗一直是无效的。在实体瘤中，免疫排斥和免疫抑制的肿瘤微环境是成功治疗的主要障碍。肿瘤中免疫细胞抗肿瘤活性低下的一个主要因素是恶劣的代谢环境。缺氧、与肿瘤和基质细胞的营养竞争，以及包括乳酸在内的有害废物的积累，对抗肿瘤免疫细胞构成了巨大的限制。目前正在开发许多策略来利用肿瘤细胞的代谢弱点，希望这些策略也能减轻代谢引起的免疫抑制。虽然原则上很有希望，特别是与免疫疗法相结合，但这些策略需要仔细研究其对抗肿瘤免疫细胞的影响，因为这些免疫细胞与肿瘤细胞有一些共同的关键代谢特性。在此，我们概述了寻求解决肿瘤或免疫细胞中的乳酸代谢以释放抗肿瘤免疫反应的策略，从而为那些目前无法治疗的肿瘤患者提供治疗选择。
参考文献
Heuser, C., Renner, K., Kreutz, M., & Gattinoni, L. (2023).
Targeting lactate metabolism for cancer immunotherapy - a matter of
precision. Seminars in cancer biology, 88, 32–45. https://doi.org/10.1016/j.semcancer.2022.12.001.
