Clear cell Renal Cell Carcinoma (RCC) represents 85% of kidney cancers and 3% of adult cancers. The majority of RCCs present an inactivation of the VHL gene inducing the constitutive stabilization of HIF-1/2 transcription factors and leading to the overexpression the pro-inflammatory cytokines like ERL+CXCL exerting their actions via the CXCR1/2 receptors and of pro-angiogenic factors such as VEGFA. VEGFA promotes pathological angiogenesis, making these cancers among the most vascularized. This phenotype explains the use of anti-angiogenic drugs (sunitinib) as first-line treatment for metastatic RCCs over the past decade. Sunitinib increased progression-free survival without increasing overall survival, unlike immunotherapy. The first line treatment at now immunotherapies (nivolumab (anti-PD-1) + ipilimumab (anti-CTLA4)). Immunotherapy has resulted in long-term "remissions” but only 30% of patients are responsive to immunotherapy1. From these observations, the following objective arises: 1- Targeting all the players in the tumor niche to increase the effectiveness of immunotherapy: use of a home-made CXCR1/2 inhibitor 2- Non-invasive prediction of immunotherapy efficacy: towards precision medicine This project will allow: - To propose a new therapeutic strategy targeting all the actors of the tumor niche (RCC, endothelial cells, M2 macrophages and fibroblasts) and promoting the effectiveness of immunotherapy - To define a plasma signature at diagnosis to predict the resistance to immunotherapy. The ultimate goal of this project is to combine immunotherapy therapy with innovative compounds to prolong survival or induce very long-term remissions in patients with metastatic RCC.