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Simple Summary: A several immunotherapy-based combinations regimen improved overall survival, and became the new first-line standard of care for metastatic clear cell renal cell carcinoma (mccRCC) patients. However, a subset of patients, approximatively 30 to 60%, are refractory to these therapies or develop a secondary acquired resistance. Currently no validated biomarkers are available in routine practice to adapt treatment strategies. Here, we summarize the potential biological biomarkers for immune checkpoint inhibitors that may have arisen from the studies of immune checkpoints. Renal cell carcinoma (RCC) represents around 2% of cancer-related deaths worldwide per year. RCC is an immunogenic malignancy, and treatment of metastatic RCC (mRCC) has greatly improved since the advent of the new immunotherapy agents, including immune checkpoint inhibitors (ICIs). However, it should be stressed that a large proportion of patients does not respond to these therapies. There is thus an urgent need to identify predictive biomarkers of efficacy or resistance associated with ICIs or ICI/Tyrosine kinase inhibitor (TKI) combinations; this is a major challenge to achieve precision medicine for mRCC in routine practice. To identify potential biomarkers, it is necessary to improve our knowledge on the biology of immune checkpoints. A lot of efforts have been made over the last decade in the field of immuno-oncology. We summarize here the main data obtained in this field when considering mRCC. As for clinical biomarkers, clinician and scientific experts of the domain are facing difficulties in identifying such molecular entities, probably due to the complexity of immuno-oncology and the constant adaptation of tumor cells to their changing environment. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy-based combinations represent the front-line standard of care for metastatic clear cell renal cell carcinoma (mccRCC) patients. These combinations lead to an overall survival improvement and a dramatic increase of complete response rate raising the question of possible cure of mccRCC patients. This review summarizes the recent advances in RCC treatment and biological aspects underpinning a possible healing. Renal-cell carcinoma (RCC) accounts for 2% of cancer diagnoses and deaths worldwide. Clear-cell RCCs represent the vast majority (85%) of kidney cancers and are considered morphologically and genetically as immunogenic tumors. Indeed, the RCC tumoral microenvironment comprises T cells and myeloid cells in an immunosuppressive state, providing an opportunity to restore their activity through immunotherapy. Standard first-line systemic treatment for metastatic patients includes immune-checkpoint inhibitors (ICIs) targeting PD1, in combination with either another ICI or with antiangiogenic targeted therapy. During the past few years, several combinations have been approved with an overall survival benefit and overall response rate that depend on the combination. Interestingly, some patients achieve prolonged complete responses, raising the question of whether these metastatic RCC patients can be cured. This review will focus on recent therapeutic advances in RCC and the clinical and biological aspects underpinning the potential for healing. [ABSTRACT FROM AUTHOR]