Extended Data Fig. 9: Proposed model.

a, Under normal (glucose-rich) conditions, T cells can effectively glycosylate proteins in the ER while fuelling mitochondrial respiration through glycolysis. These processes endow T cells with competent effector function and anti-cancer capacity. b, In the tumour microenvironment, glucose availability could be limited and T cells may also express low levels of glucose transporters such as GLUT1. Glucose restriction not only dampens glycolysis, but also impairs optimal N-linked protein glycosylation in T cells, leading to ER stress and IRE1α–XBP1 activation. XBP1 controls the abundance of glutamine transporters in T cells that are experiencing ER stress, and consequently limits the influx of glutamine necessary to sustain mitochondrial respiration under glucose deprivation. Therefore, T cells become dysfunctional and incapable of controlling malignant progression. Disabling IRE1α–XBP1 signalling may be useful to enhance T cell mitochondrial function and anti-cancer capacity in a harsh tumour microenvironment.