As cancers progress, they produce a local environment that acts to redirect, paralyze, exhaust, or otherwise evade immune detection and destruction. The tumor microenvironment (TME) has long been characterized as a metabolic desert, depleted of essential nutrients such as glucose, oxygen, and amino acids, that starves infiltrating immune cells and renders them dysfunctional. While not incorrect, this perspective is only half the picture. The TME is not a metabolic vacuum, only consuming essential nutrients and never producing by-products. Rather, the by-products of depleted nutrients, “toxic” metabolites in the TME such as lactic acid, kynurenine, ROS, and adenosine, play an important role in shaping immune cell function and cannot be overlooked in cancer immunotherapy. Moreover, while the metabolic landscape is distinct, it is not unique, as these toxic metabolites are encountered in non-tumor tissues, where they evolutionarily shape immune cells and their response. In this Review, we discuss how depletion of essential nutrients and production of toxic metabolites shape the immune response within the TME and how toxic metabolites can be targeted to improve current cancer immunotherapies.

中文翻译：

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在荒地中战斗：有害代谢物和抗肿瘤免疫

随着癌症的进展，它们会产生一种局部环境，该环境可以重定向、麻痹、耗尽或以其他方式逃避免疫检测和破坏。长期以来，肿瘤微环境 (TME) 一直被描述为代谢沙漠，缺乏葡萄糖、氧气和氨基酸等必需营养素，使浸润的免疫细胞饥饿并使其功能失调。虽然没有错，但这种观点只是图片的一半。TME 不是新陈代谢真空，只消耗必需的营养物质，从不产生副产品。相反，营养物质耗尽的副产品，即 TME 中的“有毒”代谢物，如乳酸、犬尿氨酸、活性氧和腺苷，在塑造免疫细胞功能方面发挥着重要作用，在癌症免疫治疗中也不容忽视。此外，虽然代谢景观不同，但并非独一无二，因为这些有毒代谢物存在于非肿瘤组织中，在那里它们会进化地塑造免疫细胞及其反应。在这篇综述中，我们讨论了必需营养素的消耗和有毒代谢物的产生如何影响 TME 内的免疫反应，以及如何靶向有毒代谢物来改善当前的癌症免疫疗法。