Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing (NGS), supported by robust bioinformatics. The quest for genomics-based cancer medicine set the foundations for improved patient stratification, while unveiling a wide array of neoantigens for immunotherapy. Upfront pre-clinical and clinical studies have successfully used tumor-specific peptides in vaccines with minimal off-target effects. However, the low mutational burden presented by many lesions challenges the generalization of these solutions, requiring the diversification of neoantigen sources. Oncoproteogenomics utilizing customized databases for protein annotation by mass spectrometry (MS) is a powerful tool toward this end. Expanding the concept toward exploring proteoforms originated from post-translational modifications (PTMs) will be decisive to improve molecular subtyping and provide potentially targetable functional nodes with increased cancer specificity. Walking through the path of systems biology, we highlight that alterations in protein glycosylation at the cell surface not only have functional impact on cancer progression and dissemination but also originate unique molecular fingerprints for targeted therapeutics. Moreover, we discuss the outstanding challenges required to accommodate glycoproteomics in oncoproteogenomics platforms. We envisage that such rationale may flag a rather neglected research field, generating novel paradigms for precision oncology and immunotherapy.

在强大的生物信息学的支持下，分子辅助精准肿瘤学凭借高通量下一代测序 (NGS) 取得了巨大进展。对基于基因组学的癌症医学的探索为改善患者分层奠定了基础，同时揭示了一系列用于免疫治疗的新抗原。前期的临床前和临床研究已成功地在疫苗中使用肿瘤特异性肽，并且脱靶效应最小。然而，许多病变带来的低突变负担挑战了这些解决方案的推广，需要新抗原来源的多样化。利用定制数据库通过质谱 (MS) 进行蛋白质注释的肿瘤蛋白质基因组学是实现这一目标的强大工具。扩展这一概念以探索源自翻译后修饰（PTM）的蛋白质形式对于改善分子亚型并提供具有更高癌症特异性的潜在可靶向功能节点具有决定性作用。沿着系统生物学的道路，我们强调细胞表面蛋白质糖基化的改变不仅对癌症进展和扩散具有功能性影响，而且还为靶向治疗产生独特的分子指纹。此外，我们讨论了在肿瘤蛋白质基因组学平台中适应糖蛋白质组学所需的突出挑战。我们预计，这样的基本原理可能会标志着一个相当被忽视的研究领域，为精准肿瘤学和免疫治疗产生新的范例。