Rewiring glucose metabolism in pancreatic cancer by natural compounds: implications for immune evasion and therapeutic targets.

Pancreatic ductal adenocarcinoma, which accounts for more than 90% of pancreatic cancer cases, remains one of the deadliest malignancies worldwide, with a poor 5-year survival rate of approximately 10-13% despite advances in diagnosis and treatment. Its poor prognosis is attributed to aggressive biological behavior, extensive desmoplastic stroma, profound metabolic reprogramming, and resistance to conventional therapeutic interventions. Among the hallmark metabolic alterations in PDAC, the Warburg effect enables tumor cells to sustain rapid proliferation under hypoxic and nutrient-deprived conditions. Excessive lactate accumulation within the tumor microenvironment promotes extracellular acidification, suppresses cytotoxic T-cell activity, enhances regulatory T-cell expansion, and stimulates cancer-associated fibroblast signaling, thereby facilitating immune evasion and tumour progression. Key mediators of this metabolic rewiring include glucose transporters, lactate dehydrogenase A, and monocarboxylate transporters. Consequently, integrating immunometabolic insights into therapeutic strategies has emerged as a promising approach for PDAC management. Natural compounds such as quercetin, resveratrol, curcumin, anthraquinones, and camphene have shown potential to modulate glycolytic enzymes, inhibit lactate transport, and attenuate TME-associated immunosuppression. These bioactive molecules, therefore, represent promising candidates for combination-based therapeutic interventions in PDAC. This review summarizes the molecular mechanisms underlying glucose metabolic rewiring, lactate-mediated immune evasion, and the translational potential of natural compounds as immunometabolic modulators. By highlighting the intricate interplay among glucose metabolism, lactate-driven immunosuppression, and tumor microenvironment remodeling, this review provides a mechanistic framework for the development of natural compound-based therapeutic strategies. It identifies promising directions for future preclinical and clinical investigations in PDAC.