Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100730, Beijing, China.
Key Laboratory of Research in Pancreatic Tumors, Chinese Academy of Medical Sciences, 100023, Beijing, China.
Signal Transduct Target Ther. 2023 Mar 24;8(1):139. doi: 10.1038/s41392-023-01376-w.
Research on obesity- and diabetes mellitus (DM)-related carcinogenesis has expanded exponentially since these two diseases were recognized as important risk factors for cancers. The growing interest in this area is prominently actuated by the increasing obesity and DM prevalence, which is partially responsible for the slight but constant increase in pancreatic cancer (PC) occurrence. PC is a highly lethal malignancy characterized by its insidious symptoms, delayed diagnosis, and devastating prognosis. The intricate process of obesity and DM promoting pancreatic carcinogenesis involves their local impact on the pancreas and concurrent whole-body systemic changes that are suitable for cancer initiation. The main mechanisms involved in this process include the excessive accumulation of various nutrients and metabolites promoting carcinogenesis directly while also aggravating mutagenic and carcinogenic metabolic disorders by affecting multiple pathways. Detrimental alterations in gastrointestinal and sex hormone levels and microbiome dysfunction further compromise immunometabolic regulation and contribute to the establishment of an immunosuppressive tumor microenvironment (TME) for carcinogenesis, which can be exacerbated by several crucial pathophysiological processes and TME components, such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion. This review provides a comprehensive and critical analysis of the immunometabolic mechanisms of obesity- and DM-related pancreatic carcinogenesis and dissects how metabolic disorders impair anticancer immunity and influence pathophysiological processes to favor cancer initiation.
肥胖和糖尿病（DM）相关致癌作用的研究自这两种疾病被认为是癌症的重要危险因素以来呈指数级增长。人们对这一领域越来越感兴趣，主要是因为肥胖和 DM 的患病率不断增加，这部分导致了胰腺癌（PC）发病率的轻微但持续上升。PC 是一种高度致命的恶性肿瘤，其特点是症状隐匿、诊断延迟和预后极差。肥胖和 DM 促进胰腺癌发生的复杂过程涉及它们对胰腺的局部影响以及同时发生的全身系统性变化，这些变化适合癌症的发生。这一过程涉及的主要机制包括各种营养物质和代谢物的过度积累，这些物质直接促进致癌作用，同时通过影响多种途径加剧致突变和致癌代谢紊乱。胃肠道和性激素水平的有害改变以及微生物组功能障碍进一步破坏免疫代谢调节，并有助于建立有利于致癌作用的免疫抑制肿瘤微环境（TME），这可以通过几个关键的病理生理过程和 TME 成分（如自噬、内质网应激、氧化应激、上皮-间充质转化和外泌体分泌）来加剧。这篇综述对肥胖和 DM 相关胰腺癌发生的免疫代谢机制进行了全面和批判性的分析，并剖析了代谢紊乱如何损害抗癌免疫以及影响病理生理过程以促进癌症的发生。
