The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors. T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients, hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor microenvironment. Although exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity, they are distinctly different in terms of generation, development, and metabolic and molecular regulation during tumor progression. Here, we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and progression. In addition, we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor microenvironment. Understanding these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

中文翻译：

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衰竭和衰老：肿瘤微环境中 T 细胞的两种关键功能失调状态。

大量浸润肿瘤的 T 淋巴细胞未能根除肿瘤微环境中的肿瘤细胞，主要是由于 T 细胞对肿瘤的低反应性功能障碍所致。恶性肿瘤引起的T细胞耗竭和衰老是癌症患者共存的两种重要功能失调状态，阻碍有效的抗肿瘤免疫和免疫治疗，维持抑制性肿瘤微环境。尽管衰竭和衰老的 T 细胞在抗肿瘤免疫中具有相似的功能障碍，但它们在肿瘤进展过程中的生成、发育以及代谢和分子调控方面却截然不同。在这里，我们讨论了这两种功能失调的 T 细胞的独特表型和功能特征及其在肿瘤发展和进展中的作用。此外，我们进一步讨论了在抑制性肿瘤微环境中负责控制 T 细胞耗竭和衰老的潜在分子和代谢信号通路。了解这些关键和基本特征应该有助于重新思考临床患者对当前免疫疗法的无反应性，并导致进一步开发针对不同类型功能失调的 T 细胞以增强癌症免疫疗法的新型有效策略。