The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue (including blood vessels, immune cells, fibroblasts and signaling molecules) and the extracellular matrix. Mutual interaction between cancer cells and the different components of the tumor microenvironment support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. The tumor microenvironment is in constant change because of the tumor's ability to influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The concept of the tumor microenvironment (TME) dates back to 1863 when Rudolf Virchow established a connection between inflammation and cancer. However, it was not until 1889 that Stephen Paget's seed and soil theory introduced the important role of TME in cancer metastasis, highlighting the intricate relationship between tumors and their surrounding microenvironment. The theory indicated that cancer cells have tendencies when spreading. Paget proposed that the metastases of a particular type of cancer ("the seed") often metastasizes to certain sites ("the soil") based on the similarity of the original and secondary tumor sites. In other words, just as seeds need fertile soil to grow, cancer cells require a supportive microenvironment to metastasize.

In 1928, James Ewing challenged Paget's theory with his own perspective on cancer metastasis. Ewing proposed that the ability of cancer cells to metastasize was primarily influenced by mechanical mechanisms such as anatomical and hemodynamic factors of the vascular connection, with tumor cells more likely to be trapped in the first connected organ. This viewpoint suggested that certain properties or mutations within cancer cells might dictate their metastatic potential, independent of the surrounding tissue environment. Isaiah Fidler formulated a complementary hypothesis in the 1970s, where he proposed that while the mechanical aspects of blood flow is important, metastatic colonization specifically targets certain organs, known as organotropism.

In the late 1970s, attention shifted towards understanding the role of lymphocytes within the tumor microenvironment. Reports emerged detailing the presence and activities of tumor-infiltrating T and B lymphocytes, as well as natural killer (NK) cells. Researchers observed that tumor-infiltrating T cells had both anti-tumor cytotoxicity and immune-suppressive properties. However, their cytotoxic activity was found to be lower compared to lymphocytes from distant sites, likely due to the overall immunosuppressive state in tumor-bearing individuals.

A tumor's vasculature is important to its growth, as blood vessels deliver oxygen, nutrients, and growth factors to the tumor. Tumors smaller than 1–2 mm in diameter are delivered oxygen and nutrients through passive diffusion. In larger tumors the center becomes too far away from the existing blood supply, leading the tumor microenvironment to become hypoxic and acidic. Angiogenesis is upregulated to feed the cancer cells and is linked to tumor malignancy.

In hypoxic environments the tissue sends out signals called hypoxia inducible factors (HIFs) that can stimulate nearby endothelial cells to secrete factors such as vascular endothelial growth factor (VEGF). VEGF activates the endothelial cells, which begins the process of angiogenesis, where new blood vessels emerge from pre-existing vasculature. The blood vessel formed in the tumor environment often does not mature properly, and as a result the vasculature formed in the tumor microenvironment differs from that of normal tissue. The blood vessels formed are often "leaky" and tortuous, with a compromised blood flow. As tumors cannot grow large without proper vasculature, sustained angiogenesis is therefore considered one of the hallmarks of cancer.

In later stages of tumor progression endothelial cells can differentiate into carcinoma associated fibroblasts, which furthers metastasis.

The enhanced permeability and retention effect is the observation that the vasculature of tumors tend to accumulate macromolecules in the blood stream to a greater extent than in normal tissue. This is due to the "leaky" nature of the vasculature around tumors, and a lacking lymphatic system. The permeable vasculature allows for easier delivery of therapeutic drugs to the tumor, and the lacking lymphatic vessels contribute to an increased retention. The permeable vasculature is thought to have several causes, including insufficient pericytes and a malformed basement membrane.