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 tumors 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 signaling, metabolism, chromatin organization, 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 (DOI: 10.1093/pcmedi/pbag014) on May 1, 2026, in Precision Clinical Medicine , researchers from the National Clinical Research Center 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 Center, summarized 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 tumor initiation, metastasis, immune evasion, and therapeutic resistance by altering key proteins and pathways. Phosphorylation can amplify cancer-promoting signaling; acetylation and methylation can reshape chromatin and transcription; ubiquitination and SUMOylation can control protein stability; and glycosylation can influence membrane signaling, immune recognition, and circulating biomarkers. Emerging PTMs, including lactylation, palmitoylation, β-hydroxybutyrylation, citrullination, and malonylation, further expand this regulatory landscape. Second, the authors emphasize PTM crosstalk, in which different modifications cooperate or compete on the same protein or pathway. This network-level rewiring can stabilize malignant signaling, weaken tumor-suppressive programs, 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 tumor cell state, complementing genomic and transcriptomic information and, in some contexts, offering improved association with treatment response and immune regulation. By analyzing PTM writers, erasers, readers, substrates, and modification sites as an integrated regulatory network, researchers may improve the discovery of candidate biomarkers and reveal signaling dependencies or potentially targetable vulnerabilities associated with tumor 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 tumors adapt—and where they can be stopped.
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References
DOI
Original Source URL
https://doi.org/10.1093/pcmedi/pbag014
Funding information
This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant No. 2024ZD0531100), Science and Technology Project of Sichuan Province (grant No. 2024YFFK0099), National Clinical Research Center for Geriatrics of West China Hospital (grant No. Z2024JC002), and West China Hospital 1.3.5 project for disciplines of excellence (grant No. ZYYC23013).
About Precision Clinical Medicine
Precision Clinical Medicine ( PCM ) commits itself to the combination of precision medical research and clinical application. PCM is an international, peer-reviewed, open-access journal that publishes original research articles, reviews, clinical trials, methodologies, opinions in the field of precision medicine in a timely manner. By doing so, the journal aims to provide new theories, methods, and evidence for disease diagnosis, treatment, prevention and prognosis, so as to establish a communication platform for clinicians and researchers that will impact practice of medicine. The journal covers all aspects of precision medicine, which uses novel means of diagnosis, treatment and prevention tailored to the needs of a patient or a sub-group of patients based on the specific genetic, phenotypic, or psychosocial characteristics. Clinical conditions include cancer, infectious disease, inherited diseases, complex diseases, rare diseases, etc. The journal is now indexed in ESCI, Scopus, PubMed Central, etc., with an impact factor of 5.0 (JCR2024, Q1). For further information, please refer to the journal homepage: https://academic.oup.com/pcm.
Precision Clinical Medicine
Not applicable
Protein modification systems as cancer biomarkers and therapeutic targets
1-May-2026
The authors declare that they have no competing interests.