Metabolic regulations by p53 in tumour suppression: from cell-intrinsic homeostasis to microenvironmental control

Stephanie Gurres

Yuhui Lu

Marcel Leist

Ivano Amelio

1,*

*Correspondence to: Ivano Amelio, Chair of Systemic Toxicology, Department of Biology, University of Konstanz, Konstanz 78464, Germany. E-mail: Ivano.amelio@uni-konstanz.de

EXO. 2026;1:202624. 10.70401/EXO.2026.0023

Received: June 30, 2026Accepted: October 28, 2026Published: October 28, 2026

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

The transcription factor p53, widely known as the “guardian of the genome”, is a central tumour suppressor that coordinates cellular responses to stress. Upon DNA damage and other perturbations, p53 activates transcriptional programs that promote cell-cycle arrest, senescence, and apoptosis. However, it has become increasingly clear that these canonical pathways alone do not fully account for the tumour-suppressive functions of p53. A growing body of evidence instead highlights metabolic regulation as a major component of the p53 network. p53 coordinates cellular metabolism to preserve genomic and redox homeostasis, regulate adaptation to metabolic stress, and influence cell-fate decisions through multiple forms of regulated cell death. Beyond cell-intrinsic effects, p53-dependent metabolic programs also shape the tumour microenvironment by modulating nutrient availability, immune-cell function, and intercellular signalling. In this review, we discuss how p53 regulates metabolism at both cell-intrinsic and cell-extrinsic levels and how these functions contribute to tumour suppression. We further examine how distinct p53 mutations reprogram metabolic pathways and alter the tumour-suppressive activities of wild-type p53, emphasizing the context dependence and functional heterogeneity of mutant p53. Together, these findings position metabolic regulation as a central and multifaceted component of p53 biology with important implications for understanding tumour development and therapeutic vulnerability.

Keywords

p53, metabolism regulation, cell death, genomic integrity, tumour suppressor

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Gurres S, Lu Y, Leist M, Amelio I. Metabolic regulations by p53 in tumour suppression: from cell-intrinsic homeostasis to microenvironmental control. EXO. 2026;1:202624. https://doi.org/10.70401/EXO.2026.0023