Chronic High-Fat Diet Does Not Alter Overall Cancer Incidence in Trp53R270H/+ Mice.

Obesity is a complex chronic disease characterized by excessive adiposity and multiple comorbidities, including an elevated risk of several cancers. Despite long-standing epidemiologic links, the causal relationship between body mass index and reduced cancer survival remains controversial, underscoring the need to define how obesity-related factors-such as chronic high-fat diet (HFD) exposure-influence tumor development in the context of defined oncogenic lesions. Here, we report the effects of chronic HFD-induced obesity on cancer progression in Trp53R270H/+ mice, a model of human Li-Fraumeni syndrome characterized by spontaneous multicancer susceptibility. Surprisingly, despite rapid, sustained, and highly penetrant obesity, more than 1 year of HFD had no significant effect on overall survival, tumor burden, or tumor spectrum across more than 20 anatomic sites in Trp53-mutant mice. Crucially, we did identify a single, tissue-specific exception in the lung, with HFD-fed animals showing increased prevalence of lung tumors that correlated with unique, diet-specific changes in Trp53 allelic and protein profiles. Notably, chronic HFD in this model triggered adipose-specific, not systemic, inflammation. These robust findings, replicated independently in two cohorts totaling 359 mice, suggest that Trp53R270H-driven multicancer syndrome is largely refractory to HFD-driven acceleration. Our results provide evidence that chronic diet-induced obesity does not universally enhance tumorigenesis, highlighting the complexity, tissue specificity, and context-dependent nature of obesity-cancer interactions. SIGNIFICANCE: Obesity is widely linked to cancer risk, yet causality remains debated. Using large, longitudinal cohorts of Li-Fraumeni Trp53R270H/+ mice, this study shows that chronic HFD-induced obesity does not broadly accelerate tumor burden or shorten survival, revealing strong tissue specificity, with lung cancer as a notable exception.