Metabolic crosstalk in the bladder tumor microenvironment: lactate shuttling, amino acid dependency, and...

The bladder tumor microenvironment is a complex ecosystem composed of tumor cells, stromal cells, immune cells, and the extracellular matrix. Metabolic reprogramming and intercellular metabolic crosstalk within this microenvironment play a central role in tumor progression and immune evasion. This review systematically elucidates the three-dimensional interaction network among lactate shuttling, amino acid dependency, and immune checkpoint regulation in the bladder cancer microenvironment. It untangles how metabolites such as lactate, tryptophan, and glutamine directly suppress effector T-cell function and promote the activation of immunosuppressive cells, including regulatory T cells and tumor-associated macrophages, through mechanisms involving nutrient deprivation, signal transduction, and epigenetic modifications. Studies have revealed that lactate, transported via the MCT1/MCT4/CD147 complex, establishes a lactate-glutamine metabolic cycle between tumor and stromal cells. This cycle not only supports tumor proliferation but also significantly inhibits the immune response by acidifying the microenvironment and activating key signaling pathways. Concurrently, metabolic imbalances of amino acids such as arginine, cysteine, and serine contribute to immune cell dysfunction and synergize with the expression of immune checkpoint molecules to reinforce an immunosuppressive state. Clinical data indicate that metabolism-related biomarkers, including high MCT4 expression and elevated urinary lactate concentration, are closely associated with poor prognosis and resistance to immunotherapy. Furthermore, bladder cancers of different molecular subtypes and stages exhibit significant metabolic heterogeneity, underscoring the need to develop precise metabolic intervention strategies. Future research should integrate single-cell multi-omics and spatial metabolomics technologies to construct high-resolution microenvironmental maps, develop non-invasive monitoring systems based on metabolic biomarkers, and promote the clinical translation of combination treatment plans targeting metabolic crosstalk. These efforts will provide new avenues for achieving precise and personalized therapy for bladder cancer.