Microenvironmental Control of Cancer Development and Therapy Resistance

The tumor microenvironment (TME) is now recognized as a central regulator of cancer initiation, progression, dissemination, and response to therapy. Beyond its structural role, the TME represents a highly dynamic and multifaceted ecosystem in which extracellular matrix (ECM) components, stromal and immune cells, and soluble factors cooperate to shape tumor cell behavior and fate.
Alterations in ECM composition, organization, and stiffness, together with aberrant activation of cell surface receptors and mechanotransduction pathways, profoundly influence intracellular signaling networks that drive tumor growth, invasion, immune evasion, and resistance to anticancer therapies. These microenvironmental cues modulate cancer cell plasticity, metabolism, and survival pathways, ultimately contributing to both intrinsic and acquired therapy resistance.
While increasing evidence highlights the impact of the TME on cancer biology, the molecular and cellular mechanisms underlying microenvironment-driven therapy resistance remain incompletely understood. This knowledge gap is particularly evident when considering the dynamic interactions between tumor cells and non-malignant components of the microenvironment, including cancer-associated fibroblasts, immune cells, endothelial cells, and circulating cells. Moreover, although most studies have focused on solid tumors, emerging data suggest that microenvironmental regulation also plays a critical role in hematological malignancies, warranting further investigation.
Recent advances in high-resolution technologies, such as single-cell and spatial omics, advanced imaging, and integrative multi-omics approaches, are opening new opportunities to dissect the complex signaling networks and cellular crosstalk within the TME. Understanding how microenvironmental signals orchestrate cancer development and therapeutic response may reveal novel biomarkers and therapeutic vulnerabilities.

The aim of this Research Topic is to collect original research articles and reviews that provide new insights into the role of the TME in cancer development and therapy resistance. We welcome contributions addressing, but not limited to, the following themes:

• Molecular mechanisms of tumor-microenvironment interactions in cancer progression and therapy resistance
• Cell-cell and cell-ECM communication pathways regulating drug sensitivity
• Cell adhesion-mediated drug resistance and mechanotransduction signaling
• ECM remodeling, matrix stiffness, and biomechanical regulation of tumor behavior
• Crosstalk between tumor cells, immune cells, and stromal components within the TME
• Role of circulating and infiltrating cells in shaping therapy-resistant microenvironments
• Cytoskeleton remodeling and adhesion-dependent regulation of cancer cell plasticity
• Secretome and extracellular vesicle-mediated communication in the TME
• Microenvironment-derived biomarkers for diagnosis, prognosis, and therapeutic stratification
• Single-cell, spatial transcriptomics, and spatial proteomics approaches to study TME heterogeneity
• Integrative multi-omics and systems biology analyses of microenvironmental signaling networks
• Microenvironmental regulation of tumor cell migration, invasion, and metastatic dissemination
• Comparative studies of microenvironmental control in solid and hematological malignancies

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Policy Brief
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: tumor microenvironment, extracellular matrix, chemoresistance, ECM, TME, CAM-DR, multi-omics, cell-ECM interaction, cell migration, secretome, transcriptomics, proteomics

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.