Bernhard Mlecnik and coleagues examin the impact of tumor-intrinsic, microenvironmental, and immunological factors on tumor metastasis in colorectal cancer patients. They found that decreased presence of lymphatic vessels and reduced immune cytotoxicity were more strongly associated with the metastatic process than tumor-intrinsic factors such as chromosomal instability or cancer-associated mutations. These data support testing the Immunoscore as a biomarker to predict metastasis and guide therapy.