Tumors evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function 1 – 4 . However, it remains unclear how intratumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer (OvCa), an aggressive malignancy refractory to standard treatments and current immunotherapies 5 – 8 , induces Endoplasmic Reticulum (ER) stress and activation of the IRE1α-XBP1 arm of the Unfolded Protein Response (UPR) 9 , 10 in T cells to control their mitochondrial respiration and anti-tumor function. XBP1 upregulation in T cells isolated from human OvCa specimens was associated with decreased intratumoral T cell infiltration and reduced IFNG mRNA expression. Malignant ascites fluid obtained from OvCa patients inhibited glucose uptake and caused N -linked protein glycosylation defects in T cells, leading to IRE1α/XBP1-driven suppression of mitochondrial activity and IFN-γ production. Mechanistically, XBP1 induction limited the influx of glutamine necessary to sustain T cell mitochondrial respiration under glucose-deprived conditions by regulating the abundance of glutamine carriers. Restoring N -linked protein glycosylation, abrogating IRE1α-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to OvCa ascites. XBP1-deficient T cells in the metastatic OvCa milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, OvCa-bearing mice lacking XBP1 selectively in T cells demonstrated superior anti-tumor immunity, delayed malignant progression and increased overall survival. Therefore, controlling ER stress or targeting IRE1α-XBP1 signaling may help restore T cell metabolic fitness and anti-tumor capacity in cancer hosts.

Chronic obstructive pulmonary disease (COPD) is linked to both cigarette smoking and genetic determinants. We have previously identified iron-responsive element binding protein 2 (IRP2) as an important COPD susceptibility gene, with IRP2 protein increased in the lungs of individuals with COPD. Here we demonstrate that mice deficient in Irp2 were protected from cigarette smoke (CS)-induced experimental COPD. By integrating RIP-Seq, RNA-Seq, gene expression and functional enrichment clustering analysis, we identified IRP2 as a regulator of mitochondrial function in the lung. IRP2 increased mitochondrial iron loading and cytochrome c oxidase (COX), which led to mitochondrial dysfunction and subsequent experimental COPD. Frataxin-deficient mice with higher mitochondrial iron loading had impaired airway mucociliary clearance (MCC) and higher pulmonary inflammation at baseline, whereas synthesis of cytochrome c oxidase (Sco2)-deficient mice with reduced COX were protected from CS-induced pulmonary inflammation and impairment of MCC. Mice treated with a mitochondrial iron chelator or mice fed a low-iron diet were protected from CS-induced COPD. Mitochondrial iron chelation also alleviated CS-impairment of MCC, CS-induced pulmonary inflammation and CS-associated lung injury in mice with established COPD, suggesting a critical functional role and potential therapeutic intervention for the mitochondrial-iron axis in COPD.

Highlights d APEX-mapped Tau interactome at subcellular and amino acid levels in human neurons d Activity-dependent binding of Tau to synaptic vesicle proteins during Tau secretion d FTD mutations reduce Tau binding to mitochondria proteins and impair bioenergetics d Tau interactors modified by FTD mutation are downregulated in human tauopathy Authors