Role of Bladder Cancer Metabolic Reprogramming in the Effectiveness of Immunotherapy

SIMPLE SUMMARY: Up to 90% of bladder cancers originate from the cells that line the interior of the bladder and are called urothelial carcinomas (UC). Faster growth of UC leads to a higher demand for nutrients and energy than non-malignant cells. UC compensates for this high demand for energy and building blocks by upregulation of different metabolic and bioenergetic pathways, in a process which is known as metabolic reprogramming (MR). However, this MR creates an environment within the tumor that alters immune cells, which in turn reduces the effectiveness of anticancer treatments such as immunotherapy. Here, we review UC MR and its impact on immune cells in UC in order to explore research opportunities that may improve immunotherapy. We discuss the current understanding of UC MR in animal models and summarize clinical trials that are investigating metabolism as a target to enhance immunotherapy in UC patients. ABSTRACT: 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 “MR”. 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.