肿瘤异质性是指肿瘤细胞之间观察到的多样性：不同肿瘤之间（肿瘤间异质性）和单个肿瘤内（肿瘤内异质性）。这些细胞可以表现出不同的形态和表型特征，包括细胞形态的变化、转移潜力和患者治疗反应的变异性。因此，全面了解这种异质性对于破译可能具有诊断和治疗价值的肿瘤特异性机制是必要的。需要创新和多学科的方法来理解这一复杂的特征。在这种背景下，蛋白质基因组学已成为整合基因组学和蛋白质组学等组学领域的重要资源。通过结合从下一代测序（NGS）技术和质谱（MS）分析中获得的数据，蛋白质基因组学旨在提供肿瘤异质性的全面视图。这种方法揭示了与肿瘤亚型相关的分子改变和表型特征，有可能识别治疗生物标志物。取得了许多成就；然而，尽管基于蛋白质组学的方法不断取得进展，但仍然存在一些挑战：特别是敏感性和特异性的限制以及缺乏最佳研究模型。本综述强调了蛋白质基因组学对表征肿瘤表型的影响，重点关注其在不同临床和临床前模型中用于肿瘤表型表征的关键挑战和当前局限性。

Tumor heterogeneity refers to the diversity observed among tumor cells: both between different tumors (inter-tumor heterogeneity) and within a single tumor (intra-tumor heterogeneity). These cells can display distinct morphological and phenotypic characteristics, including variations in cellular morphology, metastatic potential and variability treatment responses among patients. Therefore, a comprehensive understanding of such heterogeneity is necessary for deciphering tumor-specific mechanisms that may be diagnostically and therapeutically valuable. Innovative and multidisciplinary approaches are needed to understand this complex feature. In this context, proteogenomics has been emerging as a significant resource for integrating omics fields such as genomics and proteomics. By combining data obtained from both Next-Generation Sequencing (NGS) technologies and mass spectrometry (MS) analyses, proteogenomics aims to provide a comprehensive view of tumor heterogeneity. This approach reveals molecular alterations and phenotypic features related to tumor subtypes, potentially identifying therapeutic biomarkers. Many achievements have been made; however, despite continuous advances in proteogenomics-based methodologies, several challenges remain: in particular the limitations in sensitivity and specificity and the lack of optimal study models. This review highlights the impact of proteogenomics on characterizing tumor phenotypes, focusing on the critical challenges and current limitations of its use in different clinical and preclinical models for tumor phenotypic characterization.