The tumour microenvironment (TME) is not a static landscape but a complex and adaptive ecosystem where cancer cells, immune populations, stromal elements, and vasculature continuously interact. These exchanges determine how tumours grow, evade immune surveillance, and resist therapy. Among the most defining features of this environment is hypoxia a state of low oxygen that reshapes cellular behaviour, drives metabolic reprogramming, and promotes angiogenesis and immune suppression. Understanding these interconnected dynamics has revealed that targeting the TME requires more than single-pathway interventions; it demands integrated, multi-level strategies that reflect the true biological complexity of cancer.

Our aim is to bridge the knowledge systems of ethnopharmacology and modern oncology to reveal how nature-derived compounds can intervene within the tumour microenvironment and disrupt its pathological networks. By integrating traditional medicinal insights with contemporary biomedical research, this topic seeks to highlight the therapeutic potential of bioactive molecules capable of influencing hypoxia-driven signaling, modulating immune and metabolic pathways, and reshaping the structural and functional landscape of tumours. The overarching vision is to foster an innovative dialogue between natural products and future developments – stimulating overarching collaboration and global expertise.

We invite research that deepens the understanding of how natural products and ethnopharmacological knowledge can inform innovative strategies against the tumour microenvironment. Submissions may encompass experimental, computational, or translational approaches that elucidate how bioactive compounds shape the dynamic interactions among cancer cells, immune components, and the stromal and vascular networks that sustain tumour growth.

We particularly encourage work that explores cross-disciplinary perspectives - linking molecular mechanisms with systems-level insights to reveal new therapeutic opportunities. Studies may address processes such as cellular adaptation to stress, metabolic and immune crosstalk, angiogenic and stromal remodelling, or other fundamental drivers of tumour evolution and therapy resistance. Integrative approaches that combine traditional medicinal systems with cutting-edge methods in drug delivery, multi-omics, and computational modelling are strongly encouraged.

All submissions must adhere to the Four Pillars of Best Practice in Ethnopharmacology and the ConPhyMP statement (Front. Pharmacol. 13:953205). Detailed characterization of plant materials, extraction methods, and processing steps is essential. Manuscripts lacking this information will not be considered. Authors are encouraged to use the ConPhyMP self-assessment tool prior :o submission.

Overall, this issue seeks to highlight research that advances the dialogue between nature-inspired discovery and modern oncology, illuminating pathways toward more effective, and sustainable cancer therapies.

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The Tumor Microenvironment: Mechanisms, Challenges, and Breakthrough Therapies