Adoptive T cell therapy (ACT) using ex vivo–expanded autologous tumor-infiltrating lymphocytes (TILs) can mediate complete regression of certain human cancers. The impact of TIL phenotypes on clinical success of TIL-ACT is currently unclear. Using high-dimensional analysis of human ACT products, we identified a memory-progenitor CD39-negative stem-like phenotype (CD39⁻CD69⁻) associated with complete cancer regression and TIL persistence and a terminally differentiated CD39-positive state (CD39⁺CD69⁺) associated with poor TIL persistence. Most antitumor neoantigen-reactive TILs were found in the differentiated CD39⁺ state. However, ACT responders retained a pool of CD39⁻ stem-like neoantigen-specific TILs that was lacking in ACT nonresponders. Tumor-reactive stem-like TILs were capable of self-renewal, expansion, persistence, and superior antitumor response in vivo. These data suggest that TIL subsets mediating ACT response are distinct from TIL subsets enriched for antitumor reactivity.