Cross-talk between cancer and diabetes: Exploring shared molecular pathways in cellular metabolism and signaling

Diabetes and cancer are among the most prevalent chronic diseases globally, drawing increasing attention due to their shared features of metabolic and signaling dysregulation. Epidemiological evidence indicates that type 2 diabetes significantly elevates the risk of developing multiple types of tumors. This review highlights the key molecular intersections between diabetic pathophysiology and oncogenic processes, with a focus on how hyperinsulinemia and hyperglycemia contribute to tumor initiation and progression. These effects are primarily mediated through profound metabolic reprogramming, including hyperactivation of the hexosamine biosynthetic pathway (HBP) and the accumulation of advanced glycation end-products (AGEs), which promote sustained oxidative stress and chronic inflammation. Consequently, the tumor microenvironment (TME) undergoes substantial remodeling. The metabolism and function of immune cells are disrupted, promoting immune evasion. Meanwhile, cancer cells adapt by engaging mechanisms such as diabetes-induced epigenetic reprogramming, activation of the unfolded protein response (UPR), and alterations in the gut microbiota, thereby enhancing their survival advantage. Emerging evidence suggests that anti-diabetic agents targeting these metabolic intersections exhibit dual roles in cancer therapy, offering both therapeutic potential and potential risks. To address these complexities, future efforts should conduct multi-omics technologies to dissect the metabolic heterogeneity of diabetes-associated tumors, paving the way for precise and personalized therapeutic strategies for patients with this comorbidity.