The adoptive cell transfer (ACT) of T cells targeting mutated neoantigens can cause objective responses in varieties of metastatic cancers， but the development of new T cell-based treatments relies on accurate animal models. To investigate the therapeutic effect of targeting a neoantigen with ACT， we used T cells from pmel-1 T cell receptor-transgenic mice， known to recognize a WT peptide， gp100， and a mutated version of the peptide that has higher avidity. We gene-engineered B16 cells to express the WT or mutated gp100 epitopes and found that pmel-1-specific T cells targeting a neoantigen tumor target augmented recognition as measured by IFN-γ production. Neoantigen expression by B16 also enhanced the capacity of pmel-1 T cells to trigger the complete and durable regression of large， established， vascularized tumor and required less lymphodepleting conditioning. Targeting neoantigen uncovered the possibility of using enforced expression of the IL-2Rα chain (CD25) in mutation-reactive CD8+ T cells to improve their antitumor functionality. These data reveal that targeting of "mutated-self" neoantigens may lead to improved efficacy and reduced toxicities of T cell-based cellular immunotherapies for patients with cancer.