Extracellular Regulation of Therapeutic Resistance in Solid Tumors: Tumor Ecosystem Dynamics, Immune Plasticity, and Translational Targets

Therapeutic resistance remains one of the central challenges in oncology. Across solid tumors, resistance to chemotherapy, targeted therapy, and immunotherapy rarely emerges from cancer cells alone. It develops through dynamic interactions between cancer cells, immune populations, stromal compartments, extracellular matrix components, metabolic cues, and soluble or vesicle-mediated signals within the tumor ecosystem.



Extracellular communication shapes how tumors adapt across space and time. Secreted factors, extracellular vesicles, cytokines, chemokines, metabolites, hypoxia-associated signals, and matrix-derived cues can reprogram cancer cell states, alter immune cell function, support lineage plasticity, and create niche-specific conditions that allow resistant populations to survive and expand. These processes may differ between primary and metastatic sites, and they often evolve under therapeutic pressure as tumor and immune compartments co-adapt.



Despite major advances in the study of individual resistance mechanisms, the field still needs a more integrated view of how extracellular signals connect tumor ecosystem dynamics with immune regulation and resistant cell states. Addressing this gap requires mechanistic studies that link extracellular communication with spatial heterogeneity, temporal adaptation, immune cell plasticity, cancer cell lineage transitions, and clinically relevant resistance outcomes.



This Research Topic invites original research, reviews, and perspectives that investigate extracellular mechanisms driving therapeutic resistance in solid tumors. We welcome studies that combine mechanistic depth with translational relevance across cancer models, patient-derived systems, organoids, co-culture platforms, in vivo models, and clinical samples. The aim is to define how extracellular signals establish, sustain, or reshape resistance, while identifying biomarkers and therapeutic targets that may improve treatment response across solid tumor contexts.



This Research Topic focuses on extracellular mechanisms that establish, sustain, or amplify therapeutic resistance in solid tumors, with particular interest in how these signals shape tumor ecosystem dynamics, immune regulation, and resistant cell states.



Contributions of interest include:



Mechanisms by which extracellular signaling drives resistance to chemotherapy, targeted therapy, immunotherapy, or combination therapies



Tumor–immune crosstalk under therapeutic pressure, including the co-evolution of cancer and immune compartments during resistance development



Extracellular vesicle-mediated communication and its role in cancer cell reprogramming, immune modulation, therapy escape, and resistant niche formation



Cytokine, chemokine, growth factor, and other soluble mediator signaling pathways that regulate cancer cell plasticity, immune cell states, and treatment response



Non-inflammatory extracellular cues involved in resistance, including metabolic exchange, hypoxia-associated signaling, nutrient availability, acidosis, and stress-response signaling within tumor and immune compartments



Matrix-mediated regulation of therapeutic resistance, including extracellular matrix remodeling, stromal signaling, cancer-associated fibroblast communication, mechanotransduction, and tissue architecture



Mechanisms linking extracellular signaling to lineage plasticity, cancer stem-like states, epithelial–mesenchymal transition, cell fate transitions, senescence-associated programs, and resistant cell populations



Spatial heterogeneity and temporal adaptation in resistant tumors, including niche-specific mechanisms across primary tumors, metastatic sites, and therapy-treated microenvironments



Experimental models that capture tumor ecosystem complexity, including organoids, co-culture systems, patient-derived models, spatial profiling, single-cell approaches with experimental validation, and in vivo platforms



Translational studies identifying biomarkers, therapeutic targets, or intervention strategies within extracellular signaling pathways that may improve treatment response



Studies that are purely descriptive, consist only of bioinformatic analyses without experimental validation, or lack clear mechanistic insight fall outside the scope of this collection.

Article types and fees

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

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... 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
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Technology and Code

Keywords: Therapeutic resistance, Tumor microenvironment, Extracellular signaling, Tumor immune crosstalk, Cancer cell plasticity

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.