Immune checkpoint (IC) blockade and adoptive transfer of tumor-specific T-cells (ACT) are two strategies to treat metastatic melanoma. Their combination can potentiate T-cell activation in the suppressive tumor microenvironment. However, the undesirable autoimmune effects caused by systemic injection of anti-IC remain a major drawback of this strategy. An alternative approach could be the invalidation of ACT of tumor-reactive T-cells for IC expression. For this purpose, PD-1 and TIGIT appear to be relevant candidates because their co-expression identifies highly tumor-reactive lymphocytes but limits their effectiveness within the tumor microenvironment. Using gene editing, we invalidated PDCD1 or TIGIT genes in human Melan-A-specific CD8+ T-cells and first documented the functional consequences on T-cell functions and gene expression. We further compared the anti-tumor properties of wild-type PD-1KO and TIGITKO T-cells in vitro and in a preclinical model of immunodeficient mice, followed by ex-vivo analyses of intra-tumoral T-cell infiltrate. Transcriptomic analyses revealed downregulation of cell cycle-related genes in PD-1KO T-cells, consistent with biological observations, whereas proliferative pathways were preserved in TIGITKO T-cells. Functional analyses showed that PD-1KO and TIGITKO T-cells displayed antitumor reactivity than their wild-type counterparts against targets expressing PD-1 and TIGIT ligands, in vitro and in immunodeficient mice. Consistent with their ability to proliferate in vitro, it appears that TIGITKO T-cell clones were more effective at inhibiting tumor cell proliferation in vivo and persist for up to two weeks after injection within tumors, while PD-1KO T-cell clones were no longer detectable at this time point. Taken together, these results suggest that the deletion of TIGIT in melanoma-specific T lymphocytes constitutes a valuable option for future strategies, while the consequences of PDCD1 editing on T-cell fitness could limit their in vivo persistence and anti-tumor potential.