{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang Y"],"funding":["NIAID NIH HHS","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["1025-1035"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12657239"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["647(8091)"],"pubmed_abstract":["Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies<sup>1-4</sup>. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8<sup>+</sup> exhausted T (T<sub>ex</sub>) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (T<sub>eff</sub>) and T<sub>ex</sub> cells. We identify a distinct proteotoxic stress response (PSR) in T<sub>ex</sub> cells, which we term T<sub>ex</sub>-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis<sup>5,6</sup>, T<sub>ex</sub>-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. T<sub>ex</sub>-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert T<sub>eff</sub> cells to T<sub>ex</sub> cells, and we link T<sub>ex</sub>-PSR mechanistically to persistent AKT signalling. Finally, disruption of T<sub>ex</sub>-PSR-associated chaperones in CD8<sup>+</sup> T cells improves cancer immunotherapy in preclinical models. Moreover, a high T<sub>ex</sub>-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that T<sub>ex</sub>-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy."],"journal":["Nature"],"pubmed_title":["Proteotoxic stress response drives T cell exhaustion and immune evasion."],"pmcid":["PMC12657239"],"funding_grant_id":["R01 CA282501","R35 GM150723","R01 AI170926","R01 CA262069","R21 CA267394"],"pubmed_authors":["Abdel-Hakeem MS","Song NJ","Wen H","Huang SC","Wang R","Shannon AE","Mandula JK","Ghoneim HE","Chen X","Yousif A","Wang Y","Wu W","Wang Z","Xiao T","Xin G","Ghosh G","Searle BC","Velegraki M","Beusch CM","Ma A","Dawood AS","Saadey AA","Li Z","Amankwah YS","Gordon DE"],"additional_accession":[]},"is_claimable":false,"name":"Proteotoxic stress response drives T cell exhaustion and immune evasion.","description":"Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies<sup>1-4</sup>. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8<sup>+</sup> exhausted T (T<sub>ex</sub>) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (T<sub>eff</sub>) and T<sub>ex</sub> cells. We identify a distinct proteotoxic stress response (PSR) in T<sub>ex</sub> cells, which we term T<sub>ex</sub>-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis<sup>5,6</sup>, T<sub>ex</sub>-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. T<sub>ex</sub>-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert T<sub>eff</sub> cells to T<sub>ex</sub> cells, and we link T<sub>ex</sub>-PSR mechanistically to persistent AKT signalling. Finally, disruption of T<sub>ex</sub>-PSR-associated chaperones in CD8<sup>+</sup> T cells improves cancer immunotherapy in preclinical models. Moreover, a high T<sub>ex</sub>-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that T<sub>ex</sub>-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Nov","modification":"2026-06-06T15:44:08.204Z","creation":"2026-06-02T03:09:18.557Z"},"accession":"S-EPMC12657239","cross_references":{"pubmed":["41034580"],"doi":["10.1038/s41586-025-09539-1"]}}