The article discusses the two broad categories of tumor escape mechanisms based on the cellular and molecular characteristics of the tumor microenvironment. The first category, characterized by a T cell-inflamed phenotype, involves infiltrating T cells, a broad chemokine profile, and a type I interferon signature, which indicates innate immune activation. These tumors resist immune attack through dominant inhibitory effects of immune system-suppressive pathways. The second category lacks this T cell-inflamed phenotype and resists immune attack through immune system exclusion or ignorance. The presence of distinct immune phenotypes may require distinct immunotherapeutic interventions for optimal therapeutic effect. The article also highlights the importance of understanding the underlying molecular mechanisms that explain the interpatient heterogeneity in tumor responses, including somatic differences in tumor cells, germ-line polymorphisms in immune system regulatory genes, and environmental factors such as the composition of the intestinal microbiome. Finally, the article emphasizes the clinical implications of these findings, suggesting that predictive biomarkers for response to immunotherapies and new immunotherapeutic interventions are being identified.The article discusses the two broad categories of tumor escape mechanisms based on the cellular and molecular characteristics of the tumor microenvironment. The first category, characterized by a T cell-inflamed phenotype, involves infiltrating T cells, a broad chemokine profile, and a type I interferon signature, which indicates innate immune activation. These tumors resist immune attack through dominant inhibitory effects of immune system-suppressive pathways. The second category lacks this T cell-inflamed phenotype and resists immune attack through immune system exclusion or ignorance. The presence of distinct immune phenotypes may require distinct immunotherapeutic interventions for optimal therapeutic effect. The article also highlights the importance of understanding the underlying molecular mechanisms that explain the interpatient heterogeneity in tumor responses, including somatic differences in tumor cells, germ-line polymorphisms in immune system regulatory genes, and environmental factors such as the composition of the intestinal microbiome. Finally, the article emphasizes the clinical implications of these findings, suggesting that predictive biomarkers for response to immunotherapies and new immunotherapeutic interventions are being identified.