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<p>Antidiabetic drugs have increasingly emerged as promising candidates for oncologic repurposing, given that their biological effects extend well beyond glycemic control and can influence systemic metabolism as well as tumor–microenvironment dynamics. Accumulating preclinical, translational, and clinical evidence indicates that these agents modulate key pathways central to tumor biology, including nutrient- and energy-sensing networks, mitochondrial bioenergetics, redox homeostasis, inflammatory signaling, and antitumor immunity. Across the major antidiabetic drug classes, several convergent mechanistic themes can be identified: induction of energetic stress and relative suppression of anabolic signaling (particularly mTOR), restriction of metabolite availability to tumor cells, transcriptional reprogramming of differentiation and inflammatory pathways, and modulation of immune-cell trafficking and function within the tumor microenvironment. This review integrates mechanistic, epidemiologic, and clinical evidence within a unified framework to compare the effects of different antidiabetic drug classes across tumor contexts, distinguishing settings in which signals appear more consistent from those characterized by heterogeneity or uncertainty. It further emphasizes the critical role of host metabolic phenotype, tissue-specific biology, and tumor context in shaping therapeutic outcomes. In addition, we examine practical opportunities to position these agents as biologic modifiers alongside standard cancer therapies, with particular attention to mechanism-based combination strategies, pharmacokinetic feasibility, and safety constraints. Finally, we propose a forward-looking translational roadmap centered on biomarker-informed patient selection, clinically aligned exposure targets, and context-specific trial designs to determine where metabolic repurposing can deliver durable and clinically meaningful benefit.</p> Graphical Abstract <p>Antidiabetic drug classes may influence cancer biology through shared metabolic signaling nodes—especially the AMPK–mTOR axis—as well as host metabolic and tumor microenvironment effects. Evidence strength varies across cancer types, with stronger support in selected settings and weaker or mixed evidence in others. Translational progress is limited by tumor heterogeneity, pharmacokinetic/exposure constraints, and biomarker gaps, supporting a shift toward biomarker-guided precision oncology trial designs. Color coding indicates evidence strength (green: stronger support; yellow: moderate/mixed evidence; red: weak/limited evidence)</p>

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Anti-diabetic Drugs and Cancer: Integrated Mechanisms of Tumor Suppression and Clinical Translation

  • 期刊论文

  • 发表日期：

    2026年4月6日

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  • Mahya Asadalizadeh,
  • Mohammad Kazem Molavi Rahbar,
  • Tabassom Mahmoudie,
  • Mahshid Abbasi,
  • Mitra Akbari,
  • Davoud Shakiba,
  • Aida Mohammadiun Shabestari,
  • Meysam Ebrahimifar

摘要

Antidiabetic drugs have increasingly emerged as promising candidates for oncologic repurposing, given that their biological effects extend well beyond glycemic control and can influence systemic metabolism as well as tumor–microenvironment dynamics. Accumulating preclinical, translational, and clinical evidence indicates that these agents modulate key pathways central to tumor biology, including nutrient- and energy-sensing networks, mitochondrial bioenergetics, redox homeostasis, inflammatory signaling, and antitumor immunity. Across the major antidiabetic drug classes, several convergent mechanistic themes can be identified: induction of energetic stress and relative suppression of anabolic signaling (particularly mTOR), restriction of metabolite availability to tumor cells, transcriptional reprogramming of differentiation and inflammatory pathways, and modulation of immune-cell trafficking and function within the tumor microenvironment. This review integrates mechanistic, epidemiologic, and clinical evidence within a unified framework to compare the effects of different antidiabetic drug classes across tumor contexts, distinguishing settings in which signals appear more consistent from those characterized by heterogeneity or uncertainty. It further emphasizes the critical role of host metabolic phenotype, tissue-specific biology, and tumor context in shaping therapeutic outcomes. In addition, we examine practical opportunities to position these agents as biologic modifiers alongside standard cancer therapies, with particular attention to mechanism-based combination strategies, pharmacokinetic feasibility, and safety constraints. Finally, we propose a forward-looking translational roadmap centered on biomarker-informed patient selection, clinically aligned exposure targets, and context-specific trial designs to determine where metabolic repurposing can deliver durable and clinically meaningful benefit.

Graphical Abstract

Antidiabetic drug classes may influence cancer biology through shared metabolic signaling nodes—especially the AMPK–mTOR axis—as well as host metabolic and tumor microenvironment effects. Evidence strength varies across cancer types, with stronger support in selected settings and weaker or mixed evidence in others. Translational progress is limited by tumor heterogeneity, pharmacokinetic/exposure constraints, and biomarker gaps, supporting a shift toward biomarker-guided precision oncology trial designs. Color coding indicates evidence strength (green: stronger support; yellow: moderate/mixed evidence; red: weak/limited evidence)