In a recent study published in Nature, Garcia et al. use a sophisticated approach to identify fitness-enhancing mutations for T cells that was inspired by cancer evolution.1 The identified CARD11-PIK3R3 gene fusion enhanced tumor rejection and persistence of engineered T cells in multiple tumor models and might have the potential to improve efficacy of adoptive T-cell therapies in cancer patients. The gene discussed is PIK3R3; the disease is cancer.