Esophageal (OC), gastric (GC) and colorectal (CRC) malignancies are between the digestive monitor tumors with higher occurrence and mortality because of significant molecular heterogeneity. However, such molecular panels still require refinement and are yet to provide targetable biomarkers. In parallel, outstanding advances have been made regarding targeted therapeutics and immunotherapy, paving the way for improved patient care; nevertheless, important milestones towards treatment personalization and reduced off-target effects are also to be accomplished. Exploiting the cancer glycoproteome for unique molecular fingerprints generated by dramatic alterations in protein glycosylation may provide the necessary molecular rationale towards this end. Therefore, this review presents functional and clinical evidences supporting a reinvestigation of classical serological glycan biomarkers such as sialyl-Tn (STn) and sialyl-Lewis A (SLeA) antigens from a tumor glycoproteomics perspective. We anticipate that these glycobiomarkers that have so far been employed in noninvasive cancer prognostication may hold unexplored value for patients’ management in precision oncology settings. infection; family history, age, gender, pre-neoplastic lesions; etc). The absence of molecular biomarkers with the necessary specificity and sensitivity to assist in this matter remains a tremendous obstacle for early cancer detection; ii) Need for patient NGFR stratification, mostly achieved based on the clinicopathological classification of the lesions and, most recently, moving towards the incorporation of molecular biomarkers; iii) Therapy selection and efficacy, currently based on clinicopathological features but rapidly evolving towards molecular-assisted settings capable of aiding therapy personalization and early description of responders. Healing management continues to be based on medical procedures, chemo and/or radiotherapy, encompassing serious toxicity INCB018424 supplier and limited efficiency, for advanced disease levels particularly. Nevertheless, this paradigm provides started to modification with the launch of antibody-based targeted therapeutics against crucial oncogenic cell surface area receptors and immune-check stage proteins such as for example PD-1, PD-L1 and CTLA4. CAR-T immunotherapy is certainly amongst upcoming appealing approaches also; iv) noninvasive recognition, essential for real-time monitoring of disease evolution and position through the entire span of disease. The field of liquid biopsies provides enormously evolved with the evaluation of circulating tumor DNA/miRNAs, proteins, micro and nanovesicles (exosomes as well as others) and, more recently, the study of circulating tumor cells (CTCs). The evaluation of these biomarkers in bodily fluids has improved prognostications and helped refining therapeutic selection, evaluating responses, establishing the risk of metastasis development and the detection of radiologically occult micrometastasis; v) Molecular heterogeneity INCB018424 supplier is also a critical clinical challenge. This aspect has been a major obstacle towards effective molecular-assisted oncology and the introduction of targeted therapeutics. Nevertheless, the field has experienced significant advances with next generation sequencing, which generated a significant amount of genomics and transcriptomics data that has been used to propose gastric and colorectal cancer molecular subtypes. Cancer proteomics characterization has also contributed to the identification of relevant biomarkers; however, with yet limited clinical translation; INCB018424 supplier vi) Cancer neoantigens discovery also represents a critical objective and a daunting challenge. It’ll be essential for the id of cancer-specific fingerprints with the capacity of guiding healing decision and creating effective targeted therapies and immunotherapy with not a lot of off-targeted results. The extensive integration of genomics, proteomics and transcriptomics aswell as details on post-translational adjustments, with focus on glycosylation, will end up being of essential importance for the id of relevant proteins useful nodes and targetable biomarkers on the cell-surface. The extensive interrogation of gastroesophageal and colorectal tumors using genomics and transcriptomics has recently translated into predictive molecular versions for GC and CRC, that will decisively shape upcoming scientific practice towards accuracy oncology 11 (Body ?Body11). Notably, INCB018424 supplier OC is a neglected neoplasia relating to these objectives. Furthermore, genomics has been utilized to steer proteomics research in CRC and GC envisaging targetable biomarkers and healing personalization 12, 13. This constitutes the foundations for oncoproteogenomics that lovers mass spectrometry (MS) strategies with high-throughput next-generation sequencing (NGS) to review the role of protein variants in biological processes and pathology, while identifying malignancy neoantigens for therapy development. This big drive for systems biology is usually expanding fast, being complemented with novel layers of molecular information translated by post-translational modifications (PTM), which are critical for biological systems regulation. While much research focus has been set around the role of phosphorylation, functional glycoproteomics has now exhibited that glycosylation is also critical for defining key oncogenic features such as cell motility, invasion, metastasis and immune escape 14. Alterations in protein glycosylation also decisively contribute to the activation of relevant oncogenic pathways that sustain cell survival and proliferation 14. Moreover, cancer associated changes in the composition, density and distribution of glycosites are responsible for unique molecular signatures at the cell-surface holding tremendous potential for targeted therapeutics against membrane glycoproteins 15. Two of the most analyzed glycans in OC, GC and CRC are the sialyl-Tn (STn) antigen, a short-chain glycan resulting from a premature stop in protein sialyltransferase gene 32 and mutation 33 or hypermethylation 34 of due to histone deacetylation and DNA methylation prospects INCB018424 supplier to the expression of the short isoform SLeA. This.