Beyond conventional immune-checkpoint inhibition - novel immunotherapies for renal cell carcinoma

Nat Rev Clin Oncol. 2021 Apr;18(4):199-214. doi: 10.1038/s41571-020-00455-z. Epub 2021 Jan 12.


The management of advanced-stage renal cell carcinoma (RCC) has been transformed by the development of immune-checkpoint inhibitors (ICIs). Nonetheless, most patients do not derive durable clinical benefit from these agents. Importantly, unlike other immunotherapy-responsive solid tumours, most RCCs have only a moderate mutational burden, and paradoxically, high levels of tumour CD8+ T cell infiltration are associated with a worse prognosis in patients with this disease. Building on the successes of antibodies targeting the PD-1 and CTLA4 immune checkpoints, multiple innovative immunotherapies are now in clinical development for the treatment of patients with RCC, including ICIs with novel targets, co-stimulatory pathway agonists, modified cytokines, metabolic pathway modulators, cell therapies and therapeutic vaccines. However, the successful development of such novel immune-based treatments and of immunotherapy-based combinations will require a disease-specific framework that incorporates a deep understanding of RCC immunobiology. In this Review, using the structure provided by the well-described cancer-immunity cycle, we outline the key steps required for a successful antitumour immune response in the context of RCC, and describe the development of promising new immunotherapies within the context of this framework. With this approach, we summarize and analyse the most encouraging targets of novel immune-based therapies within the RCC microenvironment, and review the landscape of emerging antigen-directed therapies for this disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / therapy*
  • Drugs, Investigational / therapeutic use
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunologic Factors / therapeutic use
  • Immunotherapy / methods
  • Immunotherapy / trends*
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / therapy*
  • Therapies, Investigational* / methods
  • Therapies, Investigational* / trends


  • Drugs, Investigational
  • Immune Checkpoint Inhibitors
  • Immunologic Factors