Numerous precedents indicate that the immune system plays a dual role in preventing or allowing tumor development, progression, and dissemination. Besides, the immune cells’ response can be modulated by different components from the tissular extracellular matrix (ECM) where they are fulfilling their functions. In turn, immune cells can participate in the organization or remodeling of the ECM. In association with other stromal cells, these components might generate a permissive tumor microenvironment (TME). A tumor induces an injury, and then the immune system and the ECM interconnect to respond. As a result of ECM and immune cells crosstalk, tumor cells could be recognized and eliminated in a process called immunosurveillance, or, despite the control of the immune system, the influence of the ECM can favor tumor progression and metastatic dissemination. In this chapter, we described how the ECM-immune response interacts during cancer immunoediting. Besides, we discuss the tissular characteristics where the immune response is working (at the local level in solid tumors or secondary lymphatic organs) for a better comprehension of the interconnection of both TME components. On the other hand, we explained the possible implications of cancer prognosis and the able tools for clinical application.