Role of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy

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Metabolic reprogramming (MR) is an upregulation of biosynthetic and bioenergetic pathways to satisfy increased energy and metabolic building block demands of tumors. This includes glycolytic activity, which deprives the tumor microenvironment (TME) of nutrients while increasing extracellular lactic acid. This inhibits cytotoxic immune activity either via direct metabolic competition between cancer cells and cytotoxic host cells or by the production of immune-suppressive metabolites such as lactate or kynurenine. Since immunotherapy is a major treatment option in patients with metastatic urothelial carcinoma (UC), MR may have profound implications for the success of such therapy. Here, we review how MR impacts host immune response to UC and the impact on immunotherapy response (including checkpoint inhibitors, adaptive T cell therapy, T cell activation, antigen presentation, and changes in the tumor microenvironment). Articles were identified by literature searches on the keywords or references to “UC and “R”. We found several promising therapeutic approaches emerging from preclinical models that can circumvent suppressive MR effects on the immune system. A select summary of active clinical trials is provided with examples of possible options to enhance the effectiveness of immunotherapy. In conclusion, the literature suggests manipulating the MR is feasible and may improve immunotherapy effectiveness in UC.

Original languageEnglish
Article number288
Pages (from-to)1-14
Number of pages14
Issue number2
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
Funding: D.T. is supported by NCI grant CA143971.

Funding Information:
D.T. is supported by NCI grant CA143971. The authors wish to thank M.F.M. Engel from the Erasmus MC Medical Library for assistance in developing the search strategies.

Publisher Copyright:
© 2021 by the authors.


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