Multidimensional characteristics of the tumor microenviron-ment and advances in therapeutic intervention strategies

• Published in: Zhejiang da xue xue bao. Journal of Zhejiang University. Medical sciences. Yi xue ban p. 1
• Main Authors: Chen, Hongdan, Zhang, Long, Li, Chong
• Format: Journal Article
• Language: Chinese; English
• Published: 16.07.2025
• ISSN: 1008-9292
• DOI: 10.3724/zdxbyxb-2025-0090

The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied "classical" TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding of the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotem-poral heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and explores their integration with precision drug delivery strategies. We highlight recent progress in therapeutic interventions targeting the classical TME, mechanical forces, and microbiota-related pathways, and propose interdisciplinary approaches aimed at facilitating the development of more personalized and effective anticancer therapies.The tumor microenvironment (TME) is a critical determinant of tumor initiation, progression, and therapeutic response. Its marked heterogeneity underscores the need for a more comprehensive understanding of its composition and function. In addition to the extensively studied "classical" TME, emerging evidence highlights the significant roles of the tumor mechanical microenvironment and the tumor microbial microenvironment in modulating treatment efficacy. These non-classical dimensions not only independently influence tumor behavior but also interact dynamically with classical TME components. Mechanical cues within the TME, including matrix stiffness and solid stress, significantly affect drug distribution and treatment efficacy, suggesting that mechanical remodeling represents a potential strategy to enhance therapeutic outcomes. Concurrently, tumor-associated microbiota and their metabolites participate in immune regulation and metabolic reprogramming, contributing to tumor development and offering novel therapeutic targets. Moreover, recent advances have broadened our understanding of the multilayered regulatory landscape of the TME through the investigation of previously underappreciated factors such as neural regulation, metabolic niche dynamics, spatiotem-poral heterogeneity, and epigenetic modulation. This review systematically summarizes the characteristics of these diverse TME dimensions and explores their integration with precision drug delivery strategies. We highlight recent progress in therapeutic interventions targeting the classical TME, mechanical forces, and microbiota-related pathways, and propose interdisciplinary approaches aimed at facilitating the development of more personalized and effective anticancer therapies.