Chemical changes added to proteins after they are made are emerging as a powerful way to understand how cancers grow, spread, evade immunity, and resist treatment.

A new review brings these changes, known as protein post-translational modifications (PTMs), into a systems-level view of cancer biology.

Rather than treating phosphorylation, acetylation, methylation, ubiquitination, glycosylation, lactylation, and other PTMs as isolated events, considering them together with their writers, erasers, readers, and modification sites as an integrated PTM system may facilitate earlier disease diagnostic, predict treatment response, and reveal new therapeutic targets for precision oncology.

Cancer has often been explained through mutations in deoxyribonucleic acid (DNA) or changes in ribonucleic acid (RNA), but these layers do not fully explain why tumours with similar genetic profiles can behave differently.

Proteins are the working machinery of cells, and PTMs can rapidly change protein activity, stability, location, and interactions.

In cancer, these modifications are frequently rewired, reshaping signalling, metabolism, chromatin organisation, immune escape, and drug resistance.

Many studies still focus on one modification, enzyme, or pathway at a time, leaving the broader regulatory system unclear.

Based on these challenges, an in-depth investigation of PTM systems as integrated cancer regulatory networks is needed.

In a review published in Precision Clinical Medicine, researchers from the National Clinical Research Centre for Geriatrics and Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and the Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Centre, summarised current evidence linking dysregulated PTM systems to cancer biomarkers and therapeutic targets.

The review, titled “Protein modification systems as cancer biomarkers and therapeutic targets,” frames PTMs as dynamic protein-control systems that connect cancer mechanisms with clinical decision-making.

The review highlights two major layers of PTM dysregulation in cancer.

First, individual PTMs can directly drive tumour initiation, metastasis, immune evasion, and therapeutic resistance by altering key proteins and pathways.

Phosphorylation can amplify cancer-promoting signalling; acetylation and methylation can reshape chromatin and transcription; ubiquitination and SUMOylation can control protein stability; and glycosylation can influence membrane signalling, immune recognition, and circulating biomarkers.

Emerging PTMs, including lactylation, palmitoylation, β-hydroxybutyrylation, citrullination, and malonylation, further expand this regulatory landscape.

Second, the authors emphasise PTM crosstalk, in which different modifications cooperate or compete on the same protein or pathway.

This network-level rewiring can stabilise malignant signalling, weaken tumour-suppressive programmes, reprogram metabolism, remodel chromatin, and support immune checkpoint activity involving programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1).

Such combined PTM signatures may explain patient heterogeneity better than single molecular markers.

The authors said the central message is that cancer should be viewed not only as a disease of altered genes, but also as a disease of altered protein regulation.

They said PTMs provide a dynamic and functional view of tumour cell state, complementing genomic and transcriptomic information and, in some contexts, offering improved association with treatment response and immune regulation.

By analysing PTM writers, erasers, readers, substrates, and modification sites as an integrated regulatory network, researchers may improve the discovery of candidate biomarkers and reveal signalling dependencies or potentially targetable vulnerabilities associated with tumour progression.
The clinical implications are broad.

PTM-based biomarkers may improve early detection, molecular subtyping, prognosis, and prediction of therapy response, especially when combined with quantitative proteomics, spatial profiling, low-input workflows, and machine learning.

Examples reviewed include glycosylated alpha-fetoprotein (AFP), phosphorylated extracellular signal-regulated kinase (ERK), exosomal PD-L1, phosphorylated SHP2 (p-SHP2), and deglycosylated PD-L1.

Therapeutically, PTM-related strategies are already represented by kinase inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors, ubiquitin–proteasome system modulators, and epigenetic therapies.

The review concludes that precision oncology may increasingly move from single-marker testing toward system-level PTM maps that show how tumours adapt—and where they can be stopped.

Source: West China Hospital of Sichuan University