Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.

Abstract

The tumour microenvironment imposes severe metabolic constraints that reshape anti-tumour immunity across the cancer-immunity cycle. Rather than serving merely as passive byproducts of tumour growth, tumour-derived metabolites and nutrient imbalances act as potent metabolic checkpoints-stage-specific barriers that disrupt the functional progression of dendritic cells (DCs) and T cells from antigen presentation to effective tumour clearance. In this review, we propose a framework that overlays the cancer-immunity cycle with major metabolic checkpoints, including glucose and amino acid competition, acidosis and lipid overload, to clarify how distinct metabolic stresses create immune bottlenecks at different stages of the anti-tumour response. We then discuss how distinct tumour metabolic phenotypes, characterized by high glycolysis, amino acid dependency or lipid dysregulation, generate local environmental stresses that differentially reprogram DC function and T cell fitness. Particular emphasis is placed on the DC-T cell axis as a critical site where multiple metabolic defects converge, destabilizing antigen presentation, co-stimulation and immunological synapse function. We further survey emerging therapeutic strategies aimed at restoring the DC-T cell axis and effective anti-tumour immunity, ranging from small-molecule metabolic inhibitors to metabolically engineered adoptive cell therapies designed to function in hostile microenvironments. Finally, we highlight emerging technologies such as single-cell and spatial multi-omics, real-time metabolic imaging and microphysiological systems that can resolve the spatiotemporal heterogeneity of tumour immunometabolism and support more precise immunometabolic interventions.