Romesser, P. | bioRxiv Science

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↗

bioRxiv2025

Integrated histopathologic modeling of detailed tumor subtypes and actionable biomarkers

Accurate cancer subtyping with accompanying molecular characterization is critical for precision oncology. While machine learning approaches have been applied to both digital pathology and cancer genomics, previous work has been limited in sample size and has typically aggregated granular cancer subtypes into coarse groupings, likely obfuscating informative molecular and prognostic associations and phenotypic variation of more detailed tumor subtypes. Accordingly, we collated 378,123 hematoxylin and eosin (H&E)-stained whole-slide images (WSIs) with matched targeted DNA clinical sequencing results and OncoTree detailed cancer subtypes from a real-world cohort of 71,142 patients. Using this scaled, granular dataset and a cancer subtype knowledge graph, we developed Mosaic: a family of calibrated machine learning models using H&E WSI embeddings to classify tumors and identify molecular phenotypes across 163 detailed subtypes. The cancer subtyping module (Aeon) achieved an area under the receiver operating characteristic curve (AUROC) of 0.992 overall, with 161/163 subtypes reaching an AUROC [≥] 0.90 and improved performance over a state-of-the-art genomics-based classifier. The genomic inference module (Paladin) achieved an AUROC [≥] 0.80 for 167 pairs of detailed subtypes and genomic targets. We further used the learned histopathologic representations to i) identify key associations of the histopathologic embeddings with clinical biomarkers; ii) identify unsupervised sub-clusters of tumors with genomic determinants of tumor phenotype; iii) specify granular diagnoses for cancers of unknown primary, evaluated by genomic associations and expected clinical outcome distributions; iv) annotate functional significance for variants of uncertain significance (VUS); and v) identify cases that mimic the phenotypic effect of known DNA variants on H&E in the absence of detectable DNA alterations. Taken together, this work advances our understanding of phenotypic variation of granular tumor subtypes, their relevance to enhanced diagnostics, and their potential utility in risk stratification with multimodal machine learning in cancer.

cancer biology↗