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Immunotherapies have revolutionized cancer treatment, particularly through the use of immune checkpoint inhibitors (ICIs), which restore effective anti-tumor responses mediated by T cells. They are now widely used in the treatment of urological cancers, especially clear-cell renal cell carcinoma (ccRCC), the most frequent renal cancer subtype (75% of cases) and the leading cause of associated mortality. Although ICIs targeting checkpoints such as PD-1/PD-L1 or CTLA-4 have transformed the treatment of advanced disease, a significant proportion of patients (75%) remain non-responders. It is therefore critical to identify novel therapeutic targets. The HLA-G/ILT2 checkpoint has emerged as a promising alternative. HLA-G is a non-classical MHC-I molecule that inhibits both innate and adaptive immunity via its receptor ILT2, expressed by multiple immune cell subsets. While absent from most healthy tissues, HLA-G is overexpressed in many tumors, including urological cancers, where it correlates with poor prognosis. In immunocompetent murine models, we demonstrated that HLA-G expression promotes the growth of human tumors, whereas blockade of HLA-G with a monoclonal antibody restores anti-tumor responses. These findings highlight HLA-G/ILT2 as a relevant therapeutic target, particularly in patients resistant to PD-1/PD-L1 inhibitors. Several clinical trials are currently ongoing to explore this axis. In this context, my PhD aimed to characterize ILT2-expressing T lymphocytes in urological cancers using approaches combining spectral flow cytometry, single-cell RNAseq data analysis and functional co-culture assays. Our results show that ILT2+ tumor-infiltrating T cells (TILs) represent a subset of terminally differentiated effector memory T lymphocytes distinct from exhausted PD-1+ TILs, which are the primary targets of current immunotherapies. ILT2+ TILs are predominantly 'bystander' T cells specific for viral antigens and therefore unable to recognize tumor cells through their TCR. Long considered passive in anti-cancer immunity, our data reveal that these ILT2+ bystanders can be activated independently of the TCR via NKG2D, in response to pro-inflammatory cytokines such as IL-15. They subsequently acquire rapid cytotoxic activity, similar to NK cells, thus demonstrating anti-tumor potential. ILT2+ T cells are also present in peripheral blood, representing an unexploited pool of cytotoxic effectors. However, their function is impaired by inhibitory HLA-G/ILT2 interaction. Importantly, we show that blockade of this axis restores their cytotoxic activity. Our findings position ILT2+ TILs as a functional cytotoxic intratumoral population, independent from exhausted PD-1+ TILs, and as an original immunotherapeutic target. The HLA-G/ILT2 axis should therefore be considered as a therapeutic pathway in urological cancers, particularly for patients who do not respond to PD-1/PD-L1 inhibitors. In this perspective, combinatorial approaches targeting both PD-1/PD-L1 and HLA-G/ILT2, as well as innovative strategies such as the development of bispecific antibodies redirecting bystander T cells, may be envisioned.