Ciobu, N. | Search bioRxiv

bioRxiv2026

A Paracrine Dietary Lipid Axis Constrains Antitumor Immunity in Liver Cancer

Overnutrition-related liver dysfunction and cancer are increasingly prevalent and highly resistant to immunotherapy. While metabolic dysregulation is a hallmark of hepatocellular carcinoma (HCC), how nutrient overload impairs antitumor immunity remains unclear. Here, we show that short-term Western diet (WD) exposure drives near-complete loss of CD8 T cell infiltration and antitumor function in HCC. We identify dietary linoleic acid (LA), the most abundant {omega}-6 fatty acid, as the dominant immunosuppressive driver. Cancer cell-restricted FADS2-mediated desaturation of LA to longer-chain {omega}-6 PUFAs drives their accumulation in the tumor interstitial fluid, suppressing infiltrating CD8 T cells via lipid peroxidation. FADS2 inhibition restores CD8 T cell function and sensitizes WD-driven HCC to PD-1-based immunotherapy. Further, the Parkinsons disease-associated deglycase DJ-1 protects LA-handling proteins from methylglyoxal-mediated glycation, sustaining tumoral immunosuppressive PUFA production. Across multiple independent human MASLD-HCC cohorts, LA metabolic activity correlates with CD8 T cell impairment, immune exclusion, and immunotherapy resistance. Overall, these studies identify a dietary lipid axis as a therapeutically actionable vulnerability in WD-associated HCC.

Cancer Biology↗

bioRxiv2026

Non-enzymatic RNA Glycation is a Metabolic Sensor of Cellular Stress

Non-enzymatic RNA modifications expand the epitranscriptome, encoding a rapid and chemistry-driven response to cellular stress. While methylglyoxal, a reactive glycolytic byproduct of metabolic stress, has been shown to modify proteins and DNA, its impact on RNA has remained unexplored. Here, we identify mRNA as a dynamic substrate of MGO, whose modification is actively regulated by DJ-1 and the glyoxalase detoxification system. We show that mRNA glycation impairs translation and engages both the integrated stress response and the ribotoxic stress pathway, culminating in compromised pancreatic {beta}-cell function and reduced insulin secretion. Notably, this phenotype is alleviated by the frontline antihyperglycemic agent metformin. Together, our findings position mRNA as a direct sensor of metabolic stress and establish RNA glycation as a mechanistic link between glycolytic imbalance, translational stress and disease.

molecular biology↗