Glucose metabolic reprogramming as a driver of immunosuppression in the tumour microenvironment.

Immunotherapy has emerged as a transformative approach to cancer treatment, yet its clinical efficacy in most solid tumours remains limited, largely because of the immunosuppressive tumour microenvironment (TME). In this context, glucose metabolic reprogramming has emerged as a central determinant of tumour progression and immune dysfunction because it not only sustains the proliferative and biosynthetic demands of malignant cells but also profoundly reshapes immune responses within the TME. Effective antitumour immunity depends on the metabolic adaptability of effector immune cells, particularly the coordinated use of glycolysis and oxidative phosphorylation to support activation, expansion and cytotoxic function. Under the nutrient-deprived, hypoxic and acidic conditions that characterize the TME, however, these cells undergo metabolic restriction that progressively drives dysfunction and exhaustion. By contrast, regulatory T cells, tumour-associated macrophages and myeloid-derived suppressor cells exhibit greater metabolic plasticity, enabling their persistence and reinforcing their immunosuppressive activity. In this review, we discuss how glucose metabolic reprogramming drives immune dysfunction through several interconnected processes, including glucose competition, lactate accumulation, reciprocal regulation between glucose metabolism and cytokine signalling, glycosylation remodelling and dynamic crosstalk with immune checkpoint signalling. Collectively, these mechanisms position glucose metabolism as a pivotal immunometabolic axis linking tumour bioenergetics to immune evasion and therapeutic resistance. A deeper understanding of this regulatory network may inform the rational development of combination strategies that integrate metabolic intervention with immunotherapy, ultimately improving therapeutic precision and the durability of clinical benefit. HIGHLIGHT: Glucose metabolic reprogramming is a central driver of immunosuppression in the tumour microenvironment. Glucose competition establishes a selective bioenergetic hierarchy that constrains antitumour immunity. Lactate accumulation and reciprocal regulation with cytokine signalling amplify immunosuppressive signalling and reinforce immune exclusion. Glycosylation remodelling translates altered metabolic flux into sustained changes in receptor stability, ligand recognition and checkpoint responsiveness. Dynamic crosstalk with immune checkpoint signalling entrenches chronic immune dysfunction and therapeutic resistance.

© 2026 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.