The tumor microenvironment (TME) is a complex network of stromal cells, extracellular matrix (ECM) components, and non-cellular elements that dynamically interact with cancer cells. These interactions influence cancer cell heterogeneity, clonal evolution, and multidrug resistance, promoting tumor progression and metastasis. Stromal cells, including fibroblasts, endothelial cells, and immune cells, are hijacked by cancer cells to support their growth and survival. The TME also facilitates communication between cancer cells and non-malignant cells through soluble factors, exosomes, cell-free DNA (cfDNA), and apoptotic bodies, enabling horizontal gene transfer and tumor progression. Understanding these interactions is crucial for developing effective cancer therapies and diagnostic tools. Recent advances in 3D models and lab-on-chip devices have enabled better simulation of the TME, providing insights into cancer cell behavior and interactions. Tumor-derived circulating materials, such as CTCs, cfDNA, and exosomes, serve as novel theranostic tools for cancer diagnosis and monitoring. Targeting these interactions, including those involving pericytes, tumor endothelial cells (TECs), cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs), offers promising therapeutic strategies. For example, targeting TECs can inhibit angiogenesis and tumor growth, while targeting CAFs can reduce tumor progression and metastasis. Similarly, targeting TAMs can modulate tumor behavior and enhance immune responses. The ECM, composed of collagen, fibronectin, and other proteins, plays a critical role in tumor progression by influencing cancer cell behavior and interactions. Exosomes, derived from tumor cells, can promote metastasis and drug resistance by transferring genetic information between cells. Circulating tumor cells (CTCs) are also important in cancer progression, as they can seed new tumors and contribute to metastasis. Targeting CTCs and exosomes offers new approaches for cancer therapy and diagnosis. In summary, understanding the complex interactions within the TME is essential for developing effective cancer therapies. Advances in 3D models, lab-on-chip devices, and targeted therapies offer new opportunities to disrupt these interactions and improve cancer treatment outcomes.The tumor microenvironment (TME) is a complex network of stromal cells, extracellular matrix (ECM) components, and non-cellular elements that dynamically interact with cancer cells. These interactions influence cancer cell heterogeneity, clonal evolution, and multidrug resistance, promoting tumor progression and metastasis. Stromal cells, including fibroblasts, endothelial cells, and immune cells, are hijacked by cancer cells to support their growth and survival. The TME also facilitates communication between cancer cells and non-malignant cells through soluble factors, exosomes, cell-free DNA (cfDNA), and apoptotic bodies, enabling horizontal gene transfer and tumor progression. Understanding these interactions is crucial for developing effective cancer therapies and diagnostic tools. Recent advances in 3D models and lab-on-chip devices have enabled better simulation of the TME, providing insights into cancer cell behavior and interactions. Tumor-derived circulating materials, such as CTCs, cfDNA, and exosomes, serve as novel theranostic tools for cancer diagnosis and monitoring. Targeting these interactions, including those involving pericytes, tumor endothelial cells (TECs), cancer-associated fibroblasts (CAFs), and tumor-associated macrophages (TAMs), offers promising therapeutic strategies. For example, targeting TECs can inhibit angiogenesis and tumor growth, while targeting CAFs can reduce tumor progression and metastasis. Similarly, targeting TAMs can modulate tumor behavior and enhance immune responses. The ECM, composed of collagen, fibronectin, and other proteins, plays a critical role in tumor progression by influencing cancer cell behavior and interactions. Exosomes, derived from tumor cells, can promote metastasis and drug resistance by transferring genetic information between cells. Circulating tumor cells (CTCs) are also important in cancer progression, as they can seed new tumors and contribute to metastasis. Targeting CTCs and exosomes offers new approaches for cancer therapy and diagnosis. In summary, understanding the complex interactions within the TME is essential for developing effective cancer therapies. Advances in 3D models, lab-on-chip devices, and targeted therapies offer new opportunities to disrupt these interactions and improve cancer treatment outcomes.