The tumor microenvironment determines many of the hallmarks of cancer. Stromal components and malignant cells dialogue and mutually change their functional responses. Tumor infiltrating lymphocytes (TILs) are a prominent feature of solid tumors, whose presence has correlation with a better survival in cancer-patients. However TILs are severely restrained in their ability to tackle tumors as a result of immunosuppressive mechanisms. This proposal is based on the hypothesis that low levels of oxygen availability in solid tumors induce profound changes on the adaptative immune response mediated by HIF-1α and HIF-2α transcription factors. Research objectives include: 1) To study TILs behaviour under hypoxia 2) To explore the molecular mechanisms underlying the observed changes, and importantly, 3) To evaluate the impact of these changes for different immunotherapeutic strategies (monoclonal antibodies, adoptive transfers, and drugs targeting the hypoxia pathway).The state-of-the-art technical approaches to address these objectives include cutting-edge two-photon in vivo imaging to study the immune response inside hypoxic tumors, and unique-in-the-world transgenic mice to unravel the HIF-1α and HIF-2α pathway importance in T cells.This project will enable a more rational design of anti-tumor immunotherapies and could help to explain disease recurrence and identify potential targets for therapeutic interventions.