<p>OCT4 (Octamer-binding transcription factor 4, encoded by the <i>POU5F1</i> gene) is a master transcription factor for maintaining the self-renewal and pluripotency of pluripotent stem cells, as well as a pioneer factor regulating epigenetics-driven cell reprogramming and cell fate conversion. It is also detected in a variety of cancer tissues and particularly in a small subpopulation of cancer cells known as cancer stem cells (CSCs). Accumulating evidence has revealed that CSCs are a dynamic population, exhibiting shift between multipotency and differentiation states, or quiescence and proliferation states. Such cellular plasticity of CSCs is profoundly influenced by dynamic interplay between CSCs and the tumor microenvironment (TME). Here, we review recent evidence showing that OCT4 expressed in CSCs plays a multifaceted role in shaping the TME by interacting with the cellular TME components, including cancer-associated fibroblasts, tumor endothelial cells, tumor-infiltrating immune cells, as well as the non-cellular TME components, such as extracellular matrix (ECM), metabolites, soluble factors (e.g., growth factors, cytokines and chemokines), and intra-tumoral microbiota. Together, OCT4 regulates crucial processes encompassing ECM remodeling, epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and immune responses. The complex and bidirectional interactions between OCT4-expressing CSCs and the TME create a supportive niche for tumor growth, invasion, and resistance to therapy. Better understanding OCT4’s roles in such interactions can provide deeper insights into potential therapeutic strategies and targets for disrupting the supportive environment of tumors. The emerging therapies targeting OCT4 in CSCs might hold promise to resensitize therapeutic-resistant cancer cells, and to eradicate all cancer cells when combined with other therapies targeting the bulk of differentiated cancer cells as well as the TME.</p>