随着年龄的增长（即年龄相关的胸腺萎缩），或应激、感染性疾病或细胞减少治疗（如化疗/放疗）所导致的急性萎缩，胸腺功能不断下降被发现与癌症发生有关。这种增加癌症风险的关键机制是胸腺依赖性适应性免疫功能下降，这种下降负责组织免疫编辑机制和肿瘤免疫监视。近年来，一系列有趣的证据引人注目地将肥胖与癌症的发展和进展联系起来。大多数研究集中在肥胖驱动的慢性炎性反应、类固醇/性激素和脂肪激素产生以及高胰岛素血症，作为影响肿瘤微环境并推动原发性恶性肿瘤发展的主要因素。然而，有关肥胖对T细胞发育和成熟的负面影响的实验观察已经存在了半个多世纪。在这里，我们以前被忽视的中介病理学——肥胖驱动的胸腺萎缩的分子和细胞机制进行了批判性讨论，这种病理学导致了癌症的发展和进展。这些知识在儿童肥胖的背景下尤其相关，因为年轻人胸腺功能受损会导致免疫系统异常，从而使其容易患上各种儿童癌症。因此，深入了解肥胖所引起的胸腺萎缩的分子和细胞回路，对于针对高癌症风险肥胖者的靶向胸腺再生策略的合理开发可能会有所帮助。版权所有 © 2023 Elsevier Ltd.发布。

Declining thymic functions associated either with old age (i.e., age-related thymic involution), or with acute involution as a result of stress, infectious disease, or cytoreductive therapies (e.g., chemotherapy/radiotherapy), have been associated with cancer development. A key mechanism underlying such increased cancer risk is the thymus-dependent debilitation of adaptive immunity, which is responsible for orchestrating immunoediting mechanisms and tumor immune surveillance. In the past few years, a blooming set of evidence has intriguingly linked obesity with cancer development and progression. The majority of such studies has focused on obesity-driven chronic inflammation, steroid/sex hormone and adipokine production, and hyperinsulinemia, as principal factors affecting the tumor microenvironment and driving the development of primary malignancy. However, experimental observations about the negative impact of obesity on T cell development and maturation have existed for more than half a century. Here, we critically discuss the molecular and cellular mechanisms of obesity-driven thymic involution as a previously underrepresented intermediary pathology leading to cancer development and progression. This knowledge could be especially relevant in the context of childhood obesity, because impaired thymic function in young individuals leads to immune system abnormalities, and predisposes to various pediatric cancers. A thorough understanding behind the molecular and cellular circuitries governing obesity-induced thymic involution could therefore help towards the rationalized development of targeted thymic regeneration strategies for obese individuals at high risk of cancer development.Copyright © 2023. Published by Elsevier Ltd.