Fueling Early Tumorigenesis: Interplay Between the Exposome, Obesity-Driven Metabolic Dysfunction and Early-Onset...

Early-onset cancers (EOCs), defined as cancers diagnosed before the age of 50, are increasing globally. This rise cannot be fully explained by improved detection, suggesting the involvement of evolving environmental and lifestyle-related risk factors. In parallel, the global prevalence of obesity has increased substantially, particularly among younger populations. Obesity is increasingly recognized not simply as excess adiposity, but as a systemic metabolic state characterized by insulin resistance, hyperinsulinemia, chronic low-grade inflammation, altered lipid metabolism, hormonal dysregulation, microbiome disruption, and epigenetic remodeling. These perturbations create a pro-tumorigenic environment that may promote early tumor initiation and progression. Importantly, when metabolic dysfunction arises during critical developmental windows, including in utero, childhood, adolescence, and early adulthood, it may establish long-lasting biological programs that influence growth signaling, immune function, and tissue homeostasis. In this context, increasing attention has shifted toward the "exposome," defined as the totality of environmental exposures encountered across the lifespan and their interactions with biological susceptibility. These exposures may contribute to obesity-associated metabolic dysfunction and interact with one another to influence cancer risk, underscoring the multifactorial nature of EOC development. In this review, we integrate epidemiologic and mechanistic evidence linking obesity and metabolic dysfunction to EOCs, with a focus on colorectal and breast cancers. We highlight key biological pathways, including metabolic signaling, inflammation, microbiome alterations, endocrine disruption, and epigenetic reprogramming, and discuss emerging strategies for prevention and early risk stratification. Understanding the interplay between metabolic health and the exposome may provide critical insights into the prevention of EOCs in younger populations.