One approach is essentially iterative: targeting additional T cell checkpoint inhibitors such as T cell immunoglobulin domain and mucin domain-3 protein (TIM-3), lymphocyte activation gene-3 protein, T cell immunoreceptor with Ig and ITIM domains (TIGIT) or costimulatory molecules such as 4-1BB or OX40 and their ligands.6–9 Yet, the principle that can predict the engagement of a specific checkpoint over others in a cancer or a molecular subtype of cancer remains undiscovered. This evidence concerns the gene TNFRSF4 and cancer.