Targeting Metabolic Reprogramming in Bladder Cancer Immunotherapy: A Precision Medicine Approach

Abstract

Bladder cancer, as a highly heterogeneous malignant tumor of the urinary system, is significantly affected by tumor metabolic reprogramming in its response to immunotherapy. This review systematically elaborates on the molecular mechanisms of abnormal glucose and lipid metabolism in the bladder cancer microenvironment and immune escape, and discusses precision treatment strategies based on metabolic regulation. In the future, it will be necessary to combine spatiotemporal omics and artificial intelligence technologies to construct a multi-target intervention system for the metabolic-immune interaction network, promoting a paradigm shift in precision treatment for bladder cancer.

Keywords: bladder cancer; immunotherapy; metabolic reprogramming; tumor microenvironment.

Figure 1

Bladder cancer treatment flowchart. Adapted from EAU Guidelines on Bladder Cancer [9,10].

Figure 2

During the process of glucose metabolism reprogramming in urothelial carcinoma (UC), the oxygen-dependent hypoxia-inducible factor 1α (HIF-1α) and the oxygen-independent PI3K/AKT/mTOR signaling pathway drive the metabolic reprogramming in UC by regulating the activity of rate-limiting enzymes or transporters. Glucose is absorbed by cells through glucose transporters (GLUT) 1 and 3. The glycolysis process begins with hexokinase (HK) phosphorylating glucose to form glucose-6-phosphate, thereby preventing glucose from diffusing out of the cell. Glucose-6-phosphate can be dehydrogenated by glucose-6-phosphate dehydrogenase (G6PD) to enter the pentose phosphate pathway (PPP), producing pentoses such as ribose-5-phosphate for nucleotide synthesis, as well as the NADPH required for reduction processes like lipid biosynthesis. If glucose-6-phosphate is not oxidized by G6PD, it will be isomerized to fructose-6-phosphate by phosphoglucose isomerase (PGI). Subsequently, phosphofructokinase (PFK) catalyzes the phosphorylation of fructose-6-phosphate to form fructose-1,6-bisphosphate, irreversibly directing glucose-derived metabolites towards the glycolysis pathway, towards phosphoenolpyruvate. At the end of the glycolysis pathway, pyruvate kinase (PK) catalyzes the dephosphorylation of phosphoenolpyruvate (PEP) to produce pyruvate. Pyruvate is then metabolized into lactate by lactate dehydrogenase (LDH). Lactate is transported out of the cell by monocarboxylate transporters (MCT) 1 and 4, resulting in an increase in extracellular lactate concentration and acidification of the tumor microenvironment. Additionally, pyruvate can also be metabolized into acetyl-coenzyme A (acetyl-CoA), which participates in the mitochondrial tricarboxylic acid (TCA) cycle, producing ATP and intermediate metabolites that are essential for lipid and amino acid biosynthesis.

Figure 3

In the tumor microenvironment (TME), excessive lactic acid promotes the polarization of M1 macrophages to M2 macrophages, thereby suppressing the immune response and facilitating immune escape of tumor cells. Furthermore, lactic acid inhibits the migration and differentiation of monocytes into dendritic cells (DC), thus hindering the antigen presentation process and subsequent T cell activation. Lactic acid can also directly inhibit the function of CD8⁺ T cells and achieve immune suppression by promoting the proliferation of regulatory T cells (Treg).

Figure 4

In malignant cells, the biosynthesis of fatty acids and cholesterol both use acetyl-CoA as the starting substrate. Acetyl-CoA is carboxylated by the enzyme ACC1 to form malonyl-CoA, which then undergoes a multi-step condensation reaction catalyzed by fatty acid synthase (FASN), resulting in the production of a 16-carbon saturated fatty acid. Subsequently, under the action of stearoyl-CoA desaturase (SCD1), the saturated fatty acid undergoes desaturation to be converted into a monounsaturated fatty acid. The biosynthesis of cholesterol relies on the mevalonate pathway, where acetyl-CoA undergoes a series of transformation steps to form 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA), which is then reduced to mevalonate by HMG-CoA reductase (HMGCR), ultimately synthesizing cholesterol through a series of complex biochemical reactions. Furthermore, during the proliferation and development of tumor cells, the expression of fatty acid transport proteins such as CD36 and fatty acid-binding proteins (FABP) is upregulated, enhancing the activity of FASN, thereby accelerating the uptake of fatty acids and cholesterol. In summary, tumor cells regulate lipid metabolism through various mechanisms to meet their high demand for lipids and ensure an adequate supply of lipids required for their rapid proliferation. Therefore, disrupting these regulatory mechanisms may provide new strategies and potential therapeutic targets for cancer treatment.