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Dynamic tumor microenvironment remodeling in cancer therapy resistance: molecular mechanisms and translational

Xiaoying Li1,2, Shuang Dai1, Dan Cao2

  • 1Health and Management Center, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu, China.

Frontiers in Cell and Developmental Biology
|August 8, 2026
PubMed

Insights

Therapeutic resistance in solid tumors is driven by tumor microenvironment (TME) remodeling. Targeting the TME offers new strategies to overcome resistance and improve cancer treatment outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Tumor Microenvironment Research

Background:

  • Therapeutic resistance is a significant challenge in solid tumor treatment.
  • Resistance stems from both tumor cell-intrinsic factors and the tumor microenvironment (TME).
  • The TME dynamically remodels during therapy, creating resistant niches.

Purpose of the Study:

  • To review molecular mechanisms of TME remodeling driving therapeutic resistance.
  • To highlight emerging strategies targeting the TME for overcoming resistance.
  • To discuss integrating mechanistic insights with translational tools for precision oncology.

Main Methods:

  • Literature review summarizing current insights into TME remodeling.
  • Analysis of molecular mechanisms including ECM mechanotransduction, hypoxia, epigenetics, metabolism, and EVs.
  • Discussion of TME-targeting strategies and translational tools.

Main Results:

  • TME remodeling involves changes in stromal cells, immune cells, ECM, vasculature, metabolism, and signaling.
  • These changes promote immune evasion, impede drug delivery, maintain cancer stem cells, and facilitate survival.
  • Emerging strategies include stromal normalization, macrophage reprogramming, metabolic modulation, vascular normalization, and nanotechnology.

Conclusions:

  • Understanding TME remodeling is crucial for addressing multimodal therapeutic resistance.
  • Targeting the TME holds promise for enhancing cancer treatment efficacy.
  • Integrating mechanistic knowledge with advanced tools like spatial omics and organoids can guide combination therapies and patient stratification.
Keywords:
extracellular matriximmunotherapymetabolic reprogrammingtherapeutic resistancetumor microenvironment

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