Immunotherapy is an important development in cancer treatment, however, in genitourinary (GU) tumors its efficacy varies, and data suggests this may be attributed to the diversity of tumor microenvironment present in these tumors. Changes in various components and functions in the tumor microenvironment (TME) drive tumorigenesis, including changes in cancer-associated fibroblasts (CAFs), endothelial cells, immune cells, tumor-associated adipocytes, and the extracellular matrix. In addition to the TME, key metabolic enzymes driven by hypoxia-induced factors (HIFs) and other factors also plat an important role in the carcinogenesis and treatment of urinary tumors.

The energy used by endothelial cells in the tumor is mainly provided by glycolysis, which is one of the main metabolic alterations in genitourinary tumors. The free fatty acids (FAs) released by fat cells in the TME not only serve as an energy source for the metabolism of tumor cells, but they also activate vascular endothelial cells and macrophages in the TME to maintain its structure. The key factors that are closely related to TME metabolic alterations in tumors include HIFs, fatty acid synthase (FASN), and pyruvate kinase 2(PKM2), which may be potential targets for tumor therapy. Pathways of metabolites such as glutathione, tryptophan, and glycolysis have been associated with tumor diagnosis and malignant status. Glycoglycerolipid, carnitine, and tocopherol pathways have also been associated with tumor diagnosis, while the TCA cycle, nucleotide sugar, and inositol pathways have been associated with malignant status. Metabolomics is a comprehensive analysis that measures a wide range of metabolites, allowing for real-time quantification of changes in cellular metabolism. Cancer metabolism has been shown to utilize the Warburg effect, and intermediate metabolites affect cellular metabolism, cell proliferation, and immunosuppression. The measurement of metabolite upregulation accompanying cancer progression may be a promising technique for the discovery of therapeutic targets. Metabolic reprogramming, as a hallmark of cancer, participates in the initiation and progression of genitourinary tumors. The abnormal metabolic program provides tumor cells with abundant energy, nutrients, and redox requirements to support their malignancy, and is accompanied by disrupted metabolic flexibility in the tumor microenvironment. Metabolic crosstalk between tumor cells and the tumor microenvironment further facilitates immune cell transformation and leads to immunotherapy resistance. Hence, to clarify the dysregulated tumor metabolism and tumor microenvironment, novel preventive and therapeutic applications are required.

In this Special Issue, we aim to collect articles regarding the dysregulation of metabolic programs, molecular pathways, immune cell transformation, and potential therapeutic strategies, including metabolic inhibition and immune therapy. We welcome both original research and review articles.

Potential topics include but are not limited to the following:

• TME in GU cancer
• Immunocheckpoint alternation and mechanisms in GU cancer
• Metabolic targets of GU cancer
• Metabolism of immune cells in the TMEs of GU cancer
• Metabolic abnormalities associated with immunotherapy in GU cancer
• Mechanisms of immune checkpoint inhibitor (ICI) resistance in GU cancer
• Synergistic effects of anti-metabolism and immunotherapy in GU cancer
• The impact of chemotherapy and/or radiotherapy on TME and metabolism in GU cancer
• Metabolic reprogramming in GU cancer
• Dysfunction of immune cells in GU cancer
• Immune cell transformation in GU cancer
• New targets, compounds, and drugs targeting TMEs and metabolism in GU cancer