Ortet, L. | bioRxiv Science

bioRxiv2026

Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss

Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo, establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.

cancer biology↗

bioRxiv2025

Dual inhibition of the nonsense mediated mRNA decay enhances tumour immunogenicity, drives immunoediting, and potentiates checkpoint blockade

Immune checkpoint blockade has transformed cancer therapy, but current biomarkers such as tumour mutation burden often fail to reliably predict clinical benefit. One proposed reason for this discrepancy is the activity of nonsense-mediated mRNA decay (NMD), a cellular quality-control pathway that degrades mutant transcripts, potentially reducing the presentation of neoantigens that would otherwise stimulate anti-tumour immunity. To address this, we identified publicly available small-molecule inhibitors targeting the NMD factors SMG5 and SMG7 (NMDi), which we have prioritise as the NMD components most strongly associated with NMD efficiency across TCGA tumours, and evaluated their therapeutic potential in vivo. In a syngeneic, DNA repair deficient mouse model of lung adenocarcinoma, NMDi treatment alone substantially reduced tumour burden, and its combination with anti-PD-1 therapy led to additive benefit either treatment alone. These effects were immune-dependent and specifically required CD8{square} T cells. Transcriptomic and single-cell analyses revealed that NMDi reprograms the tumour immune microenvironment, enriching for clonally expanded, cytotoxic CD8{square} T cells and altering macrophage states toward those associated with tumour regression. Whole-genome sequencing of tumours revealed that NMDi also promotes immunoediting, leading to negative selection against immunogenic mutations and coding indels, with selective pressure comparable to or greater than that induced by anti-PD-1 treatment. Guided by these results, we generated a new protein language model trained on tumour mutations that can identify neopeptides with immunogenic properties, revealing that the NMDi tumour landscape provides a rich genomic and immunopeptidomic setting for exposing neoantigens that evade immunoediting. Together, these pre-clinical and integrative genomic-transcriptomic insights position NMD inhibition as a promising immunostimulatory strategy that can potentiate immune checkpoint blockade efficacy in tumours.

cancer biology↗