Mechanisms underlying obesity-malignancy connection: a systematic narrative review.

Abstract

The association between obesity and cancer risk carries substantial public health ramifications as obesity promotes cancer advancement via many cellular and molecular mechanisms. This study utilizes Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and narrative systematic review guidelines to evaluate 221 research articles selected from an initial collection of 1,288 publications sourced from multiple databases. Obesity-driven cancer risk is linked to hormonal imbalances including increased oestrogen levels that heighten the likelihood of breast and endometrial cancers, and insulin resistance that activates the insulin/ Insulin and Insulin-like Growth Factor 1 (IGF-1) pathway promoting colorectal cancer progression. Chronic low-grade inflammation, metabolic dysfunction, and hypoxia in expanding adipose tissue contribute to pancreatic, oesophageal, colorectal, renal, and liver malignancies. Recent research has identified novel mechanisms that drive obesity-induced cancer progression. The adipose tissue secretome, extracellular vesicle-mediated lipid and RNA transfer, ferroptosis resistance, and metabolic reprogramming via Cluster of Differentiation 36 (CD36), Fatty Acid Binding Protein 4 (FABP4), and Carnitine Palmitoyl transferase 1A (CPT1A) create a tumour-permissive microenvironment. Obesity-induced epigenetic memory sustains cancer risk even after weight loss through persistent histone modifications (Histone H3 Lysine 4 Trimethylation (H3K4me3), Histone H3 Lysine 27 Trimethylation (H3K27me3), DNA methylation, and RNA modifications, particularly through the Fat Mass and Obesity-Associated (FTO) gene. Additionally, organ and cell size expansion increase mutation susceptibility. Emerging pathways including the Von Hippel-Lindau (VHL)-Hypoxia-Inducible Factor (HIF) axis, PR Domain Zinc Finger Protein 16 (PRDM16)/Uncoupling Protein 1 (UCP1) inhibition, Signal Transducer and Activator of Transcription 3 (STAT3)-driven FABP4 upregulation, and Yes-Associated Protein (YAP)/Transcriptional Co-Activator with PDZ-Binding Motif (TAZ) signalling, further highlight obesity's role in oncogenesis. Future research should investigate weight-loss drugs' effects on cancer pathways, expand demographic diversity, and develop biomarkers for adiposity. Integrating Mendelian randomization, multi-omics, and artificial intelligence could reveal novel therapeutic targets. A comprehensive prevention strategy combining lifestyle interventions, pharmacological therapies, and biomarker-driven diagnostics is crucial to reducing obesity-related cancer burden and improving patient outcomes.