INTRODUCTION: The tumor microenvironment (TME) plays a pivotal role in cancer progression, influencing tumor initiation, growth, invasion, metastasis, and response to therapies. This study explores the dynamic interactions within the TME, particularly focusing on self-organization-a process by which tumor cells and their microenvironment reciprocally shape one another, leading to cancer progression and resistance. Understanding these interactions can reveal new prognostic markers and therapeutic targets within the TME, such as extracellular matrix (ECM) components, immune cells, and cytokine signaling pathways. METHODS: A comprehensive search method was employed to investigate the current academic literature on TME, particularly focusing on self-organization in the context of cancer progression and resistance across the PubMed, Google Scholar, and Science Direct databases. RESULTS: Recent studies suggest that therapies that disrupt TME self-organization could improve patient outcomes by defeating drug resistance and increasing the effectiveness of conventional therapy. Additionally, this research highlights the essential of understanding the biophysical properties of the TME, like cytoskeletal alterations, in the development of more effective malignancy therapy. CONCLUSION: This review indicated that targeting the ECM and immune cells within the TME can improve therapy effectiveness. Also, by focusing on TME self-organization, we can recognize new therapeutic plans to defeat drug resistance.