Tonello Stelvio, Rolla Roberta, Tillio Paolo Amedeo, Sainaghi Pier Paolo, Colangelo Donato
Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy.
Dipartimento per lo Sviluppo Sostenibile e la Transizione Ecologica, Università del Piemonte Orientale, Piazza S. Eusebio 5, 13100 Vercelli, Italy.
Pharmaceuticals (Basel). 2025 Jun 18;18(6):915. doi: 10.3390/ph18060915.
Tumor diseases are characterized by high interindividual and intratumoral heterogeneity (ITH). The development and progression of neoplasms outline complex networks of extracellular and cellular signals that have yet to be fully elucidated. This narrative review provides a comprehensive overview of the literature related to the cellular and molecular mechanisms underlying the heterogeneity of the tumor mass. Furthermore, it examines the possible role of the tumor microenvironment in the development and support of the neoplasm, in order to highlight its potential in the construction of a diagnostic-therapeutic approach to precision medicine. Many authors underline the importance of the tumor microenvironment (TME) as it actively takes part in the growth of the neoplastic mass and in the formation of metastases and in the acquisition of resistance to anticancer drugs. In specific body districts, the ideal conditions occur for the TME establishment, particularly the inflammatory state, the recruitment of cell types, the release of specific cytokines and growth factors, hypoxic conditions. These components actively intervene by enabling tumor progression and construction of physical barriers shaped by the extracellular matrix that contribute to forming peripheral tolerance by intervention of myeloid precursors and the polarization of M2 macrophages. In recent years, ITH and the TME have assumed an important position in cancer research and pharmacology as they enable understanding the dense network of communication existing between the neoplasm and the surrounding environment, and to monitor and deepen the effects of drugs with a view to develop increasingly precise and effective therapies. In the last decade, knowledge of TME has been exploited to produce targeted molecular agents (inhibitory small molecules, monoclonal antibodies, gene therapy). Nonetheless, the bibliography shows the need to study ITH through new prognostic and predictive biomarkers (e.g., ctDNA and CTCs) and to increase its basic biology knowledge. Precision medicine is a new opportunity in the treatment of oncological diseases that is transforming the development of new drug approaches and their clinical use. Biology and biotechnologies are providing the bases for this revolution.
肿瘤疾病的特点是个体间和肿瘤内高度异质性（ITH）。肿瘤的发生和发展勾勒出细胞外和细胞信号的复杂网络，这些网络尚未完全阐明。本叙述性综述全面概述了与肿瘤块异质性背后的细胞和分子机制相关的文献。此外，它还研究了肿瘤微环境在肿瘤发生和支持中的可能作用，以突出其在构建精准医学诊断治疗方法中的潜力。许多作者强调肿瘤微环境（TME）的重要性，因为它积极参与肿瘤块的生长、转移的形成以及对抗癌药物耐药性的获得。在特定的身体部位，为TME的建立创造了理想条件，特别是炎症状态、细胞类型的募集、特定细胞因子和生长因子的释放、缺氧条件。这些成分通过促进肿瘤进展和构建由细胞外基质形成的物理屏障来积极干预，这些物理屏障通过髓样前体的干预和M2巨噬细胞的极化有助于形成外周耐受性。近年来，ITH和TME在癌症研究和药理学中占据了重要地位，因为它们有助于理解肿瘤与周围环境之间存在的密集通信网络，并监测和深化药物的作用，以期开发出越来越精确有效的疗法。在过去十年中，TME的知识已被用于生产靶向分子药物（抑制性小分子、单克隆抗体、基因治疗）。尽管如此，文献表明需要通过新的预后和预测生物标志物（如ctDNA和CTCs）来研究ITH，并增加其基础生物学知识。精准医学是肿瘤疾病治疗中的一个新机遇，正在改变新药方法的开发及其临床应用。生物学和生物技术为这场革命提供了基础。
