Pancreatic cancer (PC) is a highly malignant gastrointestinal tumor with a 5-year survival rate of less than 10 % (Siegel et al., 2022). With approximately 511,000 new cases and 467,000 deaths globally in 2022, it is the sixth leading cause of cancer-related deaths(Dizon and Annunziata, 2025). and is projected to become the second leading cause of death by 2030 (Siegel et al., 2022). Due to insidious early symptoms, most patients are diagnosed at a late stage, with only 20 % having access to surgery and the rest relying on chemotherapy, (Huang et al., 2018). The efficacy of which is often limited by drug resistance. The standard treatment for patients with resectable PDAC and no contraindications is adjuvant chemotherapy 6 months after surgery, with the mFOLFIRINOX regimen preferred. Over the past decade, preoperative multiagent chemotherapy (e.g., FOLFIRINOX and gemcitabine in combination with albumin-conjugated paclitaxel) has provided additional therapeutic options for patients with junctional resectable and locally advanced pancreatic cancer.(Stoop et al., 2024).The resistance mechanisms of common chemotherapeutic agents are listed in Table 1.

While these agents can prolong survival to some extent, their efficacy is limited by side effects and drug resistance (Conroy et al., 2018). Common side effects include severe myelosuppression, gastrointestinal toxicity, peripheral neuropathy, and fatigue, which often compromise the patient's quality of life and limit the tolerable dosage. Additionally, chemotherapy resistance remains a major barrier, further reducing the therapeutic benefit of these treatments. According to the World Health Organization (WHO) in clinical data, the overall remission rate of PC to gemcitabine is less than 15 %, with most patients relapsing and dying within a short period (Oettle et al., 2007). Drug resistance is caused by multiple factors, including abnormalities in the intracellular enzyme system, altered expression of transport proteins, anti-apoptotic effects, and enhanced DNA repair mechanisms (Dash et al., 2024; Ono et al., 2023; Xu et al., 2023a). Recent studies have also identified new mechanisms of drug resistance, making it crucial to explore these mechanisms to address the challenge of chemotherapy resistance in clinical settings.

Tumor metabolic reprogramming refers to the alteration of metabolic pathways in tumor cells to fulfill their demands for energy, biosynthetic precursors, and redox balance (DeBerardinis and Chandel, 2016). Tumor cells differ from normal cells in glucose metabolism, amino acid metabolism, and lipid metabolism (Li and Zhang, 2016). Tumor tissues exhibit increased glycolysis, inhibited tricarboxylic acid (TCA) cycle activity, and accelerated gluconeogenesis and lipid β-oxidation, enabling rapid replenishment of energy stores (Vander Heiden et al., 2009; Yoo et al., 2020b). These changes support rapid proliferation and enable tumor cells to survive in hostile microenvironments, such as hypoxia and nutrient deprivation (Vander Heiden et al., 2009; Yoo et al., 2020b). Furthermore, metabolic reprogramming interacts with oncogenic signaling pathways and epigenetic modifications, reinforcing tumor progression and therapeutic resistance. These metabolic alterations influence tumor cell differentiation, proliferation, apoptosis, and therapeutic responses, linking metabolic reprogramming to chemoresistance (Cao, 2019).

This review focuses on the role of metabolic reprogramming in PC, examining its relationship with clinical chemotherapy resistance and exploring underlying mechanisms. Additionally, it summarizes preclinical studies and drug development efforts targeting tumor metabolism, aiming to provide a theoretical foundation for improving clinical treatment strategies.