The immune system plays an important role to prevent local growth and dissemination of cancer. Therapies based on activating the immune system can result in beneficial responses in patients with cancer. In order to harness the full potential of the immune system T and NK cells need to colonize tumors as well as to display optimal tumor killing potential. We investigate the ability of T and NK cells to migrate towards tumors, to persist within the tumor microenvironment, and to maintain the ability to and recognize and kill tumor cells. We study how T and NK cells interact with cells within the tumor microenvironment and exploit cellular and molecular mechanisms of tumor-induced immunosuppression to develop improved immunotherapy regimens in patients with cancer.