Cytotechnology. 2026 Oct;78(5):179. doi: 10.1007/s10616-026-01052-1. Epub 2026 Aug 14.
ABSTRACT
Pancreatic cancer is one of the most malignant solid tumors, with a five-year survival rate of less than 10%. The therapeutic challenges primarily stem from difficulties in early diagnosis, high heterogeneity, and extensive resistance to chemotherapy, targeted therapy, and immunotherapy. Recent studies have revealed that metabolic reprogramming, a core hallmark of cancer, is a key mechanism driving the malignant phenotype of pancreatic cancer, persisting throughout its initiation, progression, and development of treatment resistance. This article systematically reviews the molecular mechanisms underlying the dysregulation of three major nutrient metabolic pathways-glucose, lipid, and amino acid metabolism-and their interconnected regulatory networks. Regarding glucose metabolism, enhanced aerobic glycolysis and PPP activation collectively support tumor growth, redox maintenance, and microenvironmental remodeling, whereas lactate accumulation further contributes to immune evasion. Lipid metabolic reprogramming is characterized by coordinated alterations in de novo synthesis, fatty acid oxidation, and cholesterol homeostasis, which collectively regulate membrane remodeling, stemness maintenance, and therapeutic resistance. Amino acid metabolism is characterized by glutamine dependency and branched-chain amino acid metabolic reprogramming, which collectively support biosynthesis, redox homeostasis, and tumor adaptation. These three major metabolic pathways do not operate in isolation but form a dynamic, interconnected network. This network confers robust metabolic plasticity and adaptability to the tumor, constituting a fundamental basis for treatment resistance. Concurrently, stromal cells and immune cells within the tumor microenvironment also undergo metabolic reprogramming, forming a metabolic symbiotic system with cancer cells that further exacerbates treatment resistance. Although combination strategies targeting metabolic pathways-such as glycolysis inhibitors combined with gemcitabine, statins synergizing with chemotherapy, or metabolic interventions combined with immunotherapy-have shown promise in preclinical models, clinical translation remains challenging. These challenges arise from multiple factors, including tumor heterogeneity, metabolic compensation, drug delivery limitations, and the complexity of the tumor microenvironment. Future efforts should integrate single-cell metabolomics, organoid models, and multimodal imaging technologies to advance precision therapy based on metabolic subtyping. Additionally, the development of novel nanodelivery systems and multi-target combination regimens is needed to bridge the gap from mechanistic understanding to clinical application. Metabolic intervention holds potential not only for advanced-stage treatment but also for chemoprevention at the precancerous lesion stage, offering a novel approach to improving the prognosis of pancreatic cancer.
PMID:42603919 | PMC:PMC13476433 | DOI:10.1007/s10616-026-01052-1