Chen Fanghua, Fu Yuandong, Bai Gaigai, Qiu Junjun, Hua Keqin
Obstetrics and Gynecology Hospital of Fudan University, Shanghai Key Lab of Reproduction and Development, Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai, China.
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China.
Front Pharmacol. 2025 Jul 7;16:1634413. doi: 10.3389/fphar.2025.1634413. eCollection 2025.
Tumor drug resistance represents a major challenge in contemporary cancer therapeutics, significantly compromising the clinical efficacy of chemotherapy, targeted therapy, and immunotherapy. While existing research has elucidated the critical role of tumor cell-intrinsic mechanisms in drug resistance-including genomic instability, persistent activation of signaling pathways and aberrant epigenetic modifications-emerging evidence highlights the crucial involvement of dynamic remodeling within the tumor microenvironment (TME) in driving therapeutic resistance. The TME fosters drug resistance through dynamic remodeling, creating hypoxic conditions, immunosuppressive networks, and metabolic stress, which collectively impair treatment response and promote therapeutic escape. Advances in multi-omics technologies now enable a comprehensive, multi-dimensional analysis of these interactions, integrating genomic, epigenomic, transcriptomic, proteomic, and metabolomic data to uncover critical molecular networks and vulnerabilities. In this review, we explore the key mechanisms by which the TME influences drug resistance, discuss how multi-omics approaches enhance our understanding of these processes and evaluate emerging therapeutic strategies aimed at reprogramming the TME to overcome resistance.
肿瘤耐药性是当代癌症治疗中的一项重大挑战，严重影响化疗、靶向治疗和免疫治疗的临床疗效。虽然现有研究已经阐明了肿瘤细胞内在机制在耐药性中的关键作用，包括基因组不稳定、信号通路的持续激活和异常的表观遗传修饰，但新出现的证据强调了肿瘤微环境（TME）内的动态重塑在推动治疗耐药性方面的关键作用。TME通过动态重塑促进耐药性，产生低氧条件、免疫抑制网络和代谢应激，这些共同损害治疗反应并促进治疗逃逸。多组学技术的进步现在能够对这些相互作用进行全面、多维度的分析，整合基因组、表观基因组、转录组、蛋白质组和代谢组数据，以揭示关键的分子网络和脆弱性。在这篇综述中，我们探讨了TME影响耐药性的关键机制，讨论了多组学方法如何增强我们对这些过程的理解，并评估旨在重新编程TME以克服耐药性的新兴治疗策略。
