Body mass index-associated transcriptomic signatures reveal immune, stromal, and metabolic rewiring in non-small cell lung cancer: Insights into the obesity paradox

Although obesity increases cancer risk, obese patients with non-small cell lung cancer (NSCLC) paradoxically exhibit better survival. The biological basis of this “ obesity paradox ” remains unclear. High-throughput profiling can reveal body mass index (BMI)-linked transcriptional networks that shape immune, metabolic, and stromal responses, clarifying whether this “obesity paradox” reflects true tumor-microenvironment interactions rather than clinical confounders.We analyzed whole-transcriptome samples from 263 NSCLC patients in the ORIEN Avatar data at The Ohio State University. Patients were stratified into Lean (BMI<25; n=93), Overweight (25≤BMI<30; n=78), and Obese (BMI≥30; n=92) groups. Differential expression (DE) analyses (Lean vs Overweight, Lean vs Obese, Overweight vs Obese) were performed across all groups. Significantly deregulated transcripts (p<0.01 and |fold-change|>1.5) were retained for downstream analyses. Canonical pathway enrichment was conducted using Ingenuity Pathway Analysis (p<0.05).Distinct BMI-dependent transcriptomic signatures emerged. In Obese vs Lean, 40 transcripts were deregulated and enriched for metabolic processes (NAD⁺ biosynthesis, non-oxidative PPP), suggesting metabolic reprogramming. Overweight vs Lean revealed 358 deregulated transcripts with upregulated immune activation (Th1/Th2, ICOS-ICOSL, IL-2 family, PI3K signaling in B cells), indicating enhanced adaptive, particularly T-cell, immunity. Obese vs Overweight revealed 304 deregulated transcripts enriched for extracellular matrix, platelet-collagen, and osteoclast signaling, implying stromal remodeling suppression in obesity. Overlap of deregulated transcripts was modest (OvsL∩OvsOw=1; OvsL∩OwvsL=7; OvsOw∩OwvsL=52; triple overlap≈0), implying group-specific biology.Our findings delineate three BMI-linked programs in NSCLC: immune activation in overweight tumors, ECM suppression and platelet signaling in obesity, and metabolic rewiring in obese versus lean tumors. Moderate adiposity appears to foster an immune-active microenvironment, whereas higher adiposity induces stromal quiescence and redox adaptation, consistent with reports of improved immunotherapy outcomes at higher BMI. The obese subgroup's ECM/platelet and NAD⁺ salvage/PPP signatures nominate combinatorial strategies (e.g., stromal or antiplatelet agents with PD-1/PD-L1 blockade, NAMPT inhibition) and suggest that BMI-associated molecular heterogeneity may contribute to the “obesity paradox.”