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The review details nutrient and metabolite accumulation, worsened mutagenic and carcinogenic metabolic disturbances, hormone and gastrointestinal imbalance, and microbiome dysfunction. It also connects these immunometabolic shifts to immunosuppressive tumor microenvironments shaped by autophagy, endoplasmic reticulum stress, oxidative stress, EMT, and exosome 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www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans)  \nREVIEW ARTICLE  \nOPEN  \nMechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review  \nRexiati Ruze 1,2,3, Jianlu Song 1,2,3, Xinpeng Yin1,2,3, Yuan Chen1,2,3, Ruiyuan Xu1,2,3, Chengcheng Wang1,2 ✉ and Yupei Zhao1,2 ✉  \n\n|  |  |  |\n| --- | --- | --- |\n|  | 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 wholebody 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, epithelialmesenchymal 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 |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  | anticancer immunity and influence pathophysiological processes to favor cancer initiation. |  |\n|  |  |  |\n|  |  |  |\n|  | Signal Transduction and Targeted Therapy (2023)8:139 ; [https://doi.org/10.1038/s41392-023-01376-w](https://doi.org/10.1038/s41392-023-01376-w) |  |\n|  |  |  |\n\nINTRODUCTION  \nAs a multifactorial consequence of socioeconomic development, the prevalence of obesity and diabetes mellitus (DM) is booming in most parts of the world, regardless of the different landscapes among nations and regions.1,2 The detrimental outcomes and threats of obesity and DM include disability, a shortened life span, and many other critical conditions affecting both physical and mental health, whether acute, chronic, or even terminal.1–6 Some of the most vital sequelae of obesity and DM include various malignancies, including pancreatic cancer (PC) .7–9 Despite its aggressiveness and lethality, the insidious symptoms of PC make employing applicable and sensitive screening methods difficult. However, etiological studies not only can help develop tools to detect PC at an early stage but also can provide decisive clues for effective prevention, which would undoubtedly benefit both cancer-free individuals and those with undiagnosed PC.  \nIn this context, the accelerated rise in the prevalence of obesity and DM and the intimidating biological behaviors of PC have inspired tremendous explorations regarding their correlations. Beyond obesity and DM being causal factors of PC, PC, in turn, can also lead to an elevation of blood glucose and reduction of body weight, manifesting as the primary symptoms of occult  \nmalignancy.10 In terms of the carcinogenic effects of obesity and DM, many clinical studies and high-quality meta-analyses have c","cbCaia80UNh9GO8a","https://ap.wps.com/l/cbCaia80UNh9GO8a","pdf",6557647,41,"English","# Introduction\n## Obesity and diabetes as global risk factors\n## Pancreatic cancer screening and etiological research\n## Immunometabolic reprogramming and tumor microenvironment\n# Mechanisms and pathways in obesity- and DM-related carcinogenesis\n## Nutrient and metabolite accumulation\n## Hormone and microbiome-driven metabolic remodeling\n## Immunosuppressive TME formation and key pathophysiological processes","[{\"question\":\"How do obesity and diabetes mellitus increase the risk of pancreatic cancer?\",\"answer\":\"They promote carcinogenesis through local pancreatic impacts and systemic metabolic reprogramming, creating a microenvironment that supports tumor initiation.\"},{\"question\":\"Which metabolic and molecular processes are highlighted in this review?\",\"answer\":\"The review emphasizes nutrient/metabolite-driven promotion of carcinogenesis, mutagenic and carcinogenic metabolic disorders, and pathway alterations affecting immunometabolic regulation.\"},{\"question\":\"How does the tumor microenvironment contribute to obesity- and DM-related pancreatic carcinogenesis?\",\"answer\":\"It describes immunosuppressive tumor microenvironments formed through processes such as autophagy, endoplasmic reticulum stress, oxidative stress, epithelial-mesenchymal transition, and exosome secretion.\"}]","Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis - a comprehensive and systematic review | PDF",1790226572,103]