Cited by 868Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

The DOI matches its Crossref record; 40 of the 40 references it cites were found in a registry or an index.

Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8 + T Cell Exhaustion

Open access

Bengsch, Bertram, Johnson, Andy L., Kurachi, Makoto, Odorizzi, Pamela M., Pauken, Kristen E., Attanasio, John, Stelekati, Erietta, McLane, Laura M., Paley, Michael A., Delgoffe, Greg M., Wherry, E. John·2016·Immunity

DOI 10.1016/j.immuni.2016.07.008PMC PMC4988919

Open this paper in CoChat — free account Open PDF

Abstract

Dynamic reprogramming of metabolism is essential for T cell effector function and memory formation. However, the regulation of metabolism in exhausted CD8(+) T (Tex) cells is poorly understood. We found that during the first week of chronic lymphocytic choriomeningitis virus (LCMV) infection, before severe dysfunction develops, virus-specific CD8(+) T cells were already unable to match the bioenergetics of effector T cells generated during acute infection. Suppression of T cell bioenergetics involved restricted glucose uptake and use, despite persisting mechanistic target of rapamycin (mTOR) signaling and upregulation of many anabolic pathways. PD-1 regulated early glycolytic and mitochondrial alterations and repressed transcriptional coactivator PGC-1α. Improving bioenergetics by overexpression of PGC-1α enhanced function in developing Tex cells. Therapeutic reinvigoration by anti-PD-L1 reprogrammed metabolism in a subset of Tex cells. These data highlight a key metabolic control event early in exhaustion and suggest that manipulating glycolytic and mitochondrial metabolism might enhance checkpoint blockade outcomes.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Integrity signals

Registry

Crossref · 10.1016/j.immuni.2016.07.008

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

1 retracted

RETRACTED: The protein LEM promotes CD8 + T cell immunity through effects on mitochondrial respiration
Okoye, I., Wang, L., Pallmer, K., Richter, K., Ichimura, T., Haas, R., Crouse, J., Choi, O., Heathcote, D. A., Lovo, E., et al. (2015) · Science · doi:10.1126/science.aaa7516 · Cited by 51 · cited 1×
“In support of this notion, improving mitochondrial OXPHOS by overexpression or gain-of-function of lymphocyte expansion molecule (lem) increased virus-specific T cell function and viral control early during clone 13 infection (Okoye et al., 2015).”
Background
Retracted
Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625 · cited 1×
“GSEA used gene sets from the Molecular Signature Database v.5.0 (Subramanian et al., 2005) including KEGG pathway gene lists obtained from http://www.genome.jp/kegg/pathway.html.”
MethodInfluential
Molecular and cellular insights into T cell exhaustion
Wherry, E. J., & Kurachi, M. (2015) · Nature Reviews Immunology · doi:10.1038/nri3862 · Cited by 4,652 · cited 3×
“Tex cells are defined by poor effector functions, high co-expression of multiple inhibitor receptors and an altered global transcriptional program compared to functional Teff or Tmem cells (Wherry and Kurachi, 2015).”
BackgroundSelf-citation
Restoring function in exhausted CD8 T cells during chronic viral infection
Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J., & Ahmed, R. (2005) · Nature · doi:10.1038/nature04444 · Cited by 4,057 · cited 1×
“PD-L1 blockade resulted in an expansion of virusspecific T cells associated with lower viral load (data not shown), as previously described (Barber et al., 2006).”
ResultSelf-citation
Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis
Chang, C.-H., Curtis, J. D., Maggi, L. B., Faubert, B., Villarino, A. V., O’Sullivan, D., Huang, S. C.-C., van der Windt, G. J. W., Blagih, J., Qiu, J., et al. (2013) · Cell · doi:10.1016/j.cell.2013.05.016 · Cited by 2,204 · cited 3×
“In addition, switching to glycolysis is directly linked to increased effector function (Chang et al., 2013; Ho et al., 2015).”
BackgroundResult
Molecular Signature of CD8+ T Cell Exhaustion during Chronic Viral Infection
Wherry, E. J., Ha, S.-J., Kaech, S. M., Haining, W. N., Sarkar, S., Kalia, V., Subramaniam, S., Blattman, J. N., Barber, D. L., & Ahmed, R. (2007) · Immunity · doi:10.1016/j.immuni.2007.09.006 · Cited by 2,103 · cited 3×
“Differences between in vitro studies and the current data might be due to differences between in vitro activated Teff-like cells and in vivo generated Tex cells that are transcriptionally and phenotypically distinct from Teff cells (Doering et al., 2012; Wherry et al., 2007).”
BackgroundResultSelf-citation
Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens
Gubin, M. M., Zhang, X., Schuster, H., Caron, E., Ward, J. P., Noguchi, T., Ivanova, Y., Hundal, J., Arthur, C. D., Krebber, W.-J., et al. (2014) · Nature · doi:10.1038/nature13988 · Cited by 1,974 · cited 2×
“PD-1 blockade in tumor models is associated with transcriptional changes in metabolic genes (Gubin et al., 2014).”
Background
CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms
Parry, R. V., Chemnitz, J. M., Frauwirth, K. A., Lanfranco, A. R., Braunstein, I., Kobayashi, S. V., Linsley, P. S., Thompson, C. B., & Riley, J. L. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.21.9543-9553.2005 · Cited by 1,931 · cited 1×
“The intracellular tail of PD-1 contains an immunotyrosine inhibitorymotif (ITIM) and an immunotyrosine switchmotif (ITSM), that can recruit phosphatases such as SHP-2, allowing dephosphorylation of key signal transducers (Chemnitz et al., 2004; Okazaki et al., 2001).”
Background
mTOR regulates memory CD8 T-cell differentiation
Araki, K., Turner, A. P., Shaffer, V. O., Gangappa, S., Keller, S. A., Bachmann, M. F., Larsen, C. P., & Ahmed, R. (2009) · Nature · doi:10.1038/nature08155 · Cited by 1,575 · cited 3×
“This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
Background
Enhancing CD8 T-cell memory by modulating fatty acid metabolism
Pearce, E. L., Walsh, M. C., Cejas, P. J., Harms, G. M., Shen, H., Wang, L.-S., Jones, R. G., & Choi, Y. (2009) · Nature · doi:10.1038/nature08097 · Cited by 1,559 · cited 1×
“This treatmentmildly reduced the number of virus-specific T cells (Figures 4B and 4C) as expected based on the role of mTOR in effector CD8+ T cell expansion (Araki et al., 2009; Pearce et al., 2009).”
Background

Flagged first, then by citations

Show all 40 references

Sorted by citations

Items 701–800 of 867

Modulating CAR-T cell exhaustion and fitness in acute myeloid leukemia: mechanistic metabolic and microenvironmental strategies
Atilla, E. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1863485 · Cited by 1
Circadian rhythm, oxidative stress, and cancer immunosuppression
Li, Y., Nepovimová, E., Wu, Q., & Kuča, K. (2026) · Archives of Toxicology · doi:10.1007/s00204-026-04500-1 · Cited by 1
“Importantly, N-AC treatment restores TCF-1 expression and improves tumor cell killing capacity, even in models resistant to anti-PD-L1 therapy (Bengsch et al. 2016; Vardhana et al. 2020).”
Mitochondrial Energy Metabolism in Cancer, Immunoregulation and Antitumour Response
Patrício, J. S., Mendes, C., & Gameiro, P. A. (2026) · Advances in experimental medicine and biology · doi:10.1007/978-3-032-12166-0_17 · Cited by 1
Metabolic cell competition in the glioblastoma tumour microenvironment: glucose, glutamine, and lactate as determinants of immune exclusion and targets for pharmacological reprogramming
Omene, E. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1849888 · Cited by 1
The RAC1 tripartite hub: coupling metabolic plasticity and immune evasion to dictate breast cancer cell fate
Lin, H., Chen, Y., & Chu, P. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118269 · Cited by 1
Metabolic aspects of adoptive immunotherapy of tumors
Kazanskiy, D. B., Silaeva, Y. Y., Kalinina, A. A., Zamkova, M. A., Khromykh, L. M., Александровна, П. Н., & Dzholokhava, L. K. (2017) · Advances in molecular oncology · doi:10.17650/2313-805x-2017-4-3-21-26 · Cited by 1
Delivery strategies for ex vivo and in vivo T-cell reprogramming
Ben‐Akiva, E., Karlsson, J. E., Tzeng, S. Y., Yu, H., & Green, J. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-323-85781-9.00002-6 · Cited by 1
Human NKG2D Ligand Regulation of NK Cell Functions and Metabolism: From Molecular Mechanisms to Therapeutics
Dhar, P. (2021) · doi:10.21985/n2-dgdr-se80 · Cited by 1
The Tox Gene Encodes Two Proteins with Distinct and Shared Roles in Gene Regulation
Yeckes, A. R., Victor, A. R., Zhu, Z., Narayanan, M., Srinivasan, B., Bruce, B., & Kaye, J. (2023) · The Journal of Immunology · doi:10.4049/jimmunol.2200659 · Cited by 1
The effects of endometrial epithelium-derived exosomes on the recruitment and activation of T Lymphocytes in the uteri of dairy cows
Hong, A. N., Zhe, S. H. I., Fu, B., Yao, X., Ni, H., Yong, G. U. O., Xiao, L., & Wang, X. (2021) · The Thai Journal of Veterinary Medicine · doi:10.56808/2985-1130.3148 · Cited by 1
Characterization of Mitoribosomal Small Subunit unit genes related immune and pharmacogenomic landscapes in renal cell carcinoma
Wei, Z., Liu, C., Liang, J., Zhou, X., Xue, K., Wang, K., & Zhang, X. (2024) · IUBMB Life · doi:10.1002/iub.2818 · Cited by 1
Clearance of Hepatitis C Virus following Immune Checkpoint Inhibitor Therapy for Hepatocellular Carcinoma: Case Report
Wilson, H., MacDonald, D. C., & Bryce, K. (2024) · Case Reports in Gastroenterology · doi:10.1159/000539646 · Cited by 2
T-Cell Metabolism and Its Dysfunction Induced by Cancer
Prado-Garcı́a, H., Sandoval-Martinez, R., & Romero‐Garcia, S. (2020) · Springer eBooks · doi:10.1007/978-3-030-30845-2_7 · Cited by 1
Harnessing metabolism for reinvigorating dysfunctional T cells in cancer
Romero‐Garcia, S., Castro‐Flores, D. A., & Prado-García, H. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822028-3.00005-4 · Cited by 1
Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis
Ferrari, C. I., & Mondelli, M. U. (2009) · Wiley eBooks · doi:10.1002/9780470747919.ch51 · Cited by 1
The 2018 American Academy of Allergy, Asthma & Immunology Foundation Faculty Development awardees
Ballas, Z. K. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.05.023 · Cited by 1
Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of oxygen reactive speciesPreprint
Lepez, A., Pirnay, T., Denanglaire, S., Pérez-Morga, D. L., Vermeersch, M., Léo, O., & Andris, F. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.06.978791 · Cited by 1
Metabolic stress and disease-stage specific basigin expression of peripheral blood immune cell subsets in COVID-19 patientsPreprint
Siska, P. J., Singer, K., Klitzke, J., Kauer, N., Decking, S.-M., Bruß, C., Matos, C., Kolodová, K., Peuker, A., Schoenhammer, G., et al. (2020) · medRxiv · doi:10.1101/2020.09.18.20194175 · Cited by 1
ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in PLWHPreprint
Calvet‐Mirabent, M., Sánchez‐Cerrillo, I., Martin-Cofreces, N. B., de la Fuente, H., Tsukalov, I., Delgado‐Arévalo, C., Calzada, M. J., Santos, I. D. L., Sanz, J., García-Fraile, L. J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.14.476403 · Cited by 1
“5 [23-70], 64% males) were provided either by the Immunology Service from Hospital de La Princesa or Centro de Transfusión of Comunidad de Madrid, Spain (Table 2) and used for comparison purposes.”
Method
The coenzyme A precursor pantethine restrains sarcoma growth through promotion of type 1 immunityPreprint
MIALLOT, R., Millet, V., Roger, A., Fenouil, R., Tardivel, C., Martin, J., Shintu, L., BERCHARD, P., Lanza, J. S., MALISSEN, B., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-2345803/v1 · Cited by 1
Editorial: T cell exhaustion; mechanisms of induction, modulation, and recovery
Abdel-Hakeem, M. S. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1122530 · Cited by 2
“Another important aspect of TEX deviation from the acute differentiation path is adopting a different metabolic lifestyle (19), which was confirmed in consequent studies (20, 21).”
Background
Altered glucose utilization and disrupted mitochondrial homeostasis in CD4 + T cells from HIV-positive women on combination anti-retroviral therapyPreprint
Akiso, M., Ameka, M., Naidoo, K. K., Langat, R., Kombo, J., Sikuku, D., Ndung’u, T., Altfeld, M. A., Anzala, O. A., & Mureithi, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.17.541113 · Cited by 1
“Additionally, our study did not measure T-cell exhaustion, but previous results suggest that a similarly distorted metabolic phenotype is an upstream indicator of T-cell exhaustion(21).”
BackgroundResultInfluential
A PD-1-ST2 axis controls Th2 effector function in tissue via a metabolic checkpointPreprint
Heieis, G. A., Everts, B., Roberts, C. W., Maizels, R. M., & Perona‐Wright, G. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.13.553117 · Cited by 1
Sequential IL-15 and TGF-β1 stimulation expands reprogrammed CD103⁺CD39⁺ effector CD8⁺T cells and enhances HIV controlPreprint
Mancebo-Pérez, C., Benítez-Martínez, A., Tsukalov, I., Grau-Expósito, J., Castellví, J., Mañalich, L., Centeno, C., Planas, B., Navarro, J., Burgos, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.09.647906 · Cited by 1
Studies of innate and adaptive lymphocytes in human liver diseases and viral infections
Zimmer, C. L. (2019) · Figshare
Advancing transcriptome analysis in models of disease and ageing
de Jong, T. V. (2019) · doi:10.33612/diss.99203371
Examining the Radiation-induced Bystander Effect (RIBE) and its Effect on Metabolism and Inflammation in Gastrointestinal Cancers
Heeran, A. B. (2021) · Arrow@dit (Dublin Institute of Technology)
NK cell-mediated immunotherapy: The exquisite role of PGC-1a in metabolic reprogramming
Gerbec, Z. J., & Malarkannan, S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-824375-6.00006-0
Targeting metabolism to potentiate NK cell-based therapies
Dhar, P., & Wu, J. D. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-824375-6.00016-3
Meta-analysis of exhausted CD8+ T cells from Homo sapiens and Mus musculus provides robust targets for immunotherapyPreprint
Zhang, L., Guo, Y., & Nishi, H. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.05.451111
Metabolic regulation of dendritic cell function and activation
Guak, H. (2021) · doi:10.82308/52296
Regulation of cellular metabolism in tumor infiltrating CD8+ T cells and its role in their dysfunction
Gemta, L. F. (2019) · Libra · doi:10.18130/v3-k04d-7r03
Spatiotemporal Co-Dependency between Macrophages and Exhausted CD8 + T Cells in CancerPreprint
Kersten, K., Hu, K. H., Combes, A. J., Samad, B., Harwin, T., Ray, A., Rao, A. A., Cai, E., Marchuk, K., Artichoker, J., et al. (2021) · SSRN Electronic Journal · doi:10.2139/ssrn.3942126
Metabolic Profile of Adaptive Immune Cells
Domínguez-Amorocho, O. A., Soto‐Heredero, G., & Mittelbrunn, M. (2021) · Springer eBooks · doi:10.1007/978-3-030-86684-6_6
PSGL-1 directs early TCR signaling to repress metabolism and promote T cell exhaustion by modulating the TCF-1/TOX axis in CD8 + T cellsPreprint
Hope, J. L., Otero, D. C., Bae, E., Stairiker, C. J., Palete, A. B., Faso, H. A., Henriquez, M. L., Seo, H., Lei, X., Wang, E. S., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.01.24.477602
“Early during the development of T cell exhaustion, CD8 + T cells demonstrate reduced respiration (OCR) and glycolysis 27 .”
Background
Faculty Opinions recommendation of CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction.
Woodland, D. L. (2019) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.735141981.793557277
Faculty Opinions recommendation of Obstacles posed by the tumor microenvironment to t cell activity: A case for synergistic therapies.
Tsokos, G. C. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.727394204.793570386
Chemoenzymatic Measurement of Cell-surface Glycan in Single-cell Multiomics: LacNAc as an ExamplePreprint
Yu, W., Zhao, X., Jalloh, A. S., Zhao, Y., Dinner, B., Yang, Y., Ouyang, S., Li, Y., Tian, T., Zhao, Z., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.01.506123
HDAC7 controls anti-viral and anti-tumor immunity by CD8 + T cellsPreprint
Yerinde, C., Keye, J., Durlanik, S., Freise, I., Nowak, F., Hsiao, H.-J., Letizia, M., Schlickeiser, S., Obermayer, B., Huck, A., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.18.508452
Assessment of the Mitochondrial Condition in CD4+ and CD8+ T-Lymphocytes from Healthy Subjects
Korolevskaya, L. B., Сайдакова, Е. В., Геннадьевна, Ш. Н., & Владимирович, Ш. К. (2022) · Cell and Tissue Biology · doi:10.1134/s1990519x22050054
“It is known that, in pathological situations, CD8+ T-lymphocytes are more prone to exhaustion than CD4+ T-lymphocytes (Bengsch et al., 2016; McLane et al., 2019; Yu et al., 2020).”
Background
The 11th Canadian Symposium on Hepatitis C Virus: ‘Getting back on track towards hepatitis C elimination’
Passos‐Castilho, A. M., Udhesister, S. T. P., Fontaine, G., Jeong, D., Dickie, M., Lund, C., Russell, R. S., & Kronfli, N. (2022) · Canadian Liver Journal · doi:10.3138/canlivj-2022-0034
Nanotechnology to Correct Mitochondrial Disorders in Cancer Diseases
Faria, R., Albuquerque, T., Neves, A. R., Sousa, Â., & Costa, D. R. B. (2022) · Springer eBooks · doi:10.1007/978-3-031-17831-3_6
The Prospects of Immunotherapy in Pancreatic Cancer
Ying, H., & Yao, W. (2022) · Springer eBooks · doi:10.1007/978-3-031-05724-3_22
Distinct transcriptional profiles of HIV- and CMV-specific CD8 T cells in HIV progressors and long-term non-progressorsPreprint
van Pul, L., Stunnenberg, M., Boeser‐Nunnink, B., Harskamp, A. M., Geijtenbeek, T. B. H., & Kootstra, N. A. (2023) · Research Square · doi:10.21203/rs.3.rs-2408098/v1
T-Cell Metabolism and Its Regulation by Checkpoint Molecules: Consequences for Cancer Immunotherapy
Romero‐Garcia, S., Mendoza, M. S., Carlos‐Reyes, Á., & Prado-Garcı́a, H. (2023) · Springer eBooks · doi:10.1007/978-3-030-80962-1_159-1
A Novel Prognostic Signature for Combined T-cell Exhaustion and Mitochondrial Dysfunction in Hepatocellular CarcinomaPreprint
Liu, J., He, M., Liu, Y., Liu, M., Wang, H., Gu, W., Gao, Y., Li, Z., & Song, H. (2023) · Research Square · doi:10.21203/rs.3.rs-2691058/v1
HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cellsPreprint
Wu, H., Zhao, X., Hochrein, S. M., Eckstein, M., Gubert, G. F., Knöpper, K., Mansilla, A. M., Öner, A., Doucet-Ladevèze, R., Schmitz, W., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.31.555662
Spatial organization and stochastic fluctuations of immune cells impact clinical responsiveness to immune checkpoint inhibitors in patients with melanomaPreprint
Giuliani, G., Stewart, W., Li, Z., Jayaprakash, C., & Das, J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.06.570410
The transcription factor IRF-5 is essential for the metabolic rewiring of CD8 T cells during chronic infectionPreprint
Mai, L. T., Swaminathan, S., Nguyen, T. H., Charpentier, T., Loucif, H., Carmona‐Pérez, L., Lamarre, A., Heinonen, K. M., Fritz, J. H., & Stäger, S. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.29.577789
Role of Kupffer cells and other immune cells
Puengel, T., & Tacke, F. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-95262-0.00024-3
YTHDF2 upregulation and relocation dictate CD8 T cell polyfunctionality in tumor immunityPreprint
Zhang, H., Luo, X.-J., Yang, W., Wu, Z., Zhao, Z., Pei, X., Zhang, X., Chen, C., Lei, J. H., Shi, Q., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.11.603088
Targeting Mitochondria in Cancer Immunotherapy: Promises and Pitfalls
Allami, P., Mortaheb, S., Aghakhani, A., & Rezaei, N. (2024) · Interdisciplinary cancer research · doi:10.1007/16833_2024_448
The role of cellular persistence in CAR T cell therapy
Menkhoff, V. D., Bernhard, S., Michaelides, S., Stock, S., & Kobold, S. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-14064-8.00029-1
Acquisition of an immunosuppressive microenvironment after CAR-T therapy drives T-cell dysfunction and resistancePreprint
Ponzo, M., Drufuca, L., Buracchi, C., Sindoni, M. M., Nucera, S., Bugarin, C., Bason, R., Rossetti, G., Bonnal, R. J. P., Meli, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.20.629119
Precise engineering of chimeric antigen receptor expression levels defines T cell identity and functionPreprint
Ramos, A., Simon, S., Siller‐Farfán, J. A., Rajan, A., Revale, S., di Castiglionchio, E. Z., Pelea, O., Fulga, T. A., Riddell, S. R., Dushek, O., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.10.637482
Immuno-cell metabolic changes in HIV-1 infection
Li, X., Jiang, Y., Zheng, X., & Shi, H. (2025) · Infectious Diseases & Immunity · doi:10.1097/id9.0000000000000159 · Cited by 1
Lack of Bcl6 promotes anti-tumor immunity by activating glycolysis to rescue CD8 T cell functionPreprint
Luan, F., Li, Y., Ning, J., Tran, J. T., Blane, T. R., Bhargava, R., Huang, Z., Xiao, C., & Nemazee, D. A. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.01.646721
Genital herpes shedding episodes associate with alterations in the spatial organization and activation of mucosal immune cellsPreprint
MacLean, F., Zemek, R. M., Tsegaye, A. T., Graham, J. B., Swarts, J. L., Vick, S. C., Potchen, N. B., Talavera, I. C., Warrier, L., Dubrulle, J., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.24.661157
Cellular Metabolism Controls Lymphocyte Activation and Differentiation
Powell, J. D., & Sun, I. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00180-0
Immunometabolism Governs T Cell Immunity
Raynor, J. L., Shi, H., & Chi, H. (2025) · Elsevier eBooks · doi:10.1016/b978-0-12-824465-4.00275-1
Astragalin inhibits hepatitis B virus through functional reconstitution of CD8+ T cells and a direct effect on HBV control
Li, H., Yang, S., Zhao, H., Zhang, J., Guo, W., Shen, T., & Han, Q. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178108
ENO2 regulates CD4 + T cell pyroptosis via mitochondrial ROS to drive immunological non-response in HIV infection
Li, S., Wang, H., Wang, P., Yang, T., Li, J., Liu, M., Fu, Y., Jiang, Y., Zhang, Z.-N., & Shang, H. (2025) · mBio · doi:10.1128/mbio.01702-25
“The MMP supports ATP production during oxidative phosphorylation, and a lower membrane potential may cause impairment of T cell mitochondrial function, increasing the level of depolarized mitochondria (38, 39), and mitochondrial damage plays a critical role in pyroptosis (26).”
Enhancing Virus-Specific T Cell Persistence: L-Arginine Supplementation Improves the Durability of CD8 + T Cells for ImmunotherapyPreprint
Tomoda, T., Kawana‐Tachikawa, A., Shimizu, S., Takahashi, S., Kanegane, H., Kamiya, T., Inoue, K., Takagi, M., & Morio, T. (2025) · Research Square · doi:10.21203/rs.3.rs-7518621/v1
Progenitor T cells drive chronic pulmonary type 2 inflammation
Kratchmarov, R., Jia, X., Nagai, J., Pacheco, G. A., Perniss, A., Bell, M. A., Gül, E., Thompson, T. W., Hayashi, H., Saghaei, S., et al. (2026) · Nature Immunology · doi:10.1038/s41590-026-02619-y
“These results suggest the presence of divergent underlying metabolic programs, of note given the bioenergetic insufficiency seen in chronic infection 78 and role of catabolism in self-renewal 79 .”
T-Cell Metabolism and Its Regulation by Checkpoint Molecules: Consequences for Cancer Immunotherapy
Romero‐Garcia, S., Mendoza, M. S., Carlos‐Reyes, Á., & Prado-Garcı́a, H. (2025) · Springer eBooks · doi:10.1007/978-3-032-00765-0_159
Tumormikromilieu des hepatozellulären Karzinoms – Schlüssel zur Therapiestratifizierung von Lebertumoren
Schlaak, A. E., Thimme, R., & Bengsch, B. (2025) · Die Onkologie · doi:10.1007/s00761-025-01854-6
Self-citation
Translational Downregulation of 5’ TOP mRNAs During T Cell ExhaustionPreprint
Pledger, E. S., Ambavaram, N., Ferguson, L., & Cate, J. H. D. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.15.694525
Additional file 1 of The immune checkpoint TIGIT/CD155 promotes the exhaustion of CD8 + T cells in TNBC through glucose metabolic reprogramming mediated by PI3K/AKT/mTOR signaling
Huang, M., Yu, X., Wang, Q., Jiang, Z., Li, X., Chen, W., & 宋传贵 (2024) · Figshare · doi:10.6084/m9.figshare.24993741
Additional file 3 of PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapy/immunotherapy combination in mouse models of lung cancer
Zhang, Y., Hu, H.-H., Zhou, S.-H., Xia, W., Zhang, Y., Zhang, J.-P., Fu, X.-L., & Yu, W. (2023) · Figshare · doi:10.6084/m9.figshare.22600454
Additional file 2 of Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma
Sun, G., Liu, C., Lu, Z., Zhang, J., Cao, H., Huang, T., Dai, M., Liu, H., Feng, T., Tang, W., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25951969
Additional file 4 of PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapy/immunotherapy combination in mouse models of lung cancer
Zhang, Y., Hu, H.-H., Zhou, S.-H., Xia, W., Zhang, Y., Zhang, J.-P., Fu, X.-L., & Yu, W. (2023) · Figshare · doi:10.6084/m9.figshare.22600457
Additional file 2 of PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapy/immunotherapy combination in mouse models of lung cancer
Zhang, Y., Hu, H.-H., Zhou, S.-H., Xia, W., Zhang, Y., Zhang, J.-P., Fu, X.-L., & Yu, W. (2023) · Figshare · doi:10.6084/m9.figshare.22600451
Additional file 1 of Metabolomics reveals ascorbic acid inhibits ferroptosis in hepatocytes and boosts the effectiveness of anti-PD1 immunotherapy in hepatocellular carcinoma
Sun, G., Liu, C., Lu, Z., Zhang, J., Cao, H., Huang, T., Dai, M., Liu, H., Feng, T., Tang, W., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25951885
Additional file 1 of Increased levels of PD1 and glycolysis in CD4+ T cells are positively associated with lymph node metastasis in OSCC
Wu, K., Han, N., Mao, Y., & Li, Y. (2023) · Figshare · doi:10.6084/m9.figshare.23292132
Additional file 5 of PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapy/immunotherapy combination in mouse models of lung cancer
Zhang, Y., Hu, H.-H., Zhou, S.-H., Xia, W., Zhang, Y., Zhang, J.-P., Fu, X.-L., & Yu, W. (2023) · Figshare · doi:10.6084/m9.figshare.22600460
Additional file 1 of PET-based radiomics visualizes tumor-infiltrating CD8 T cell exhaustion to optimize radiotherapy/immunotherapy combination in mouse models of lung cancer
Zhang, Y., Hu, H.-H., Zhou, S.-H., Xia, W., Zhang, Y., Zhang, J.-P., Fu, X.-L., & Yu, W. (2023) · Figshare · doi:10.6084/m9.figshare.22600448
Additional file 1 of Differences in genetics and microenvironment of lung adenocarcinoma patients with or without TP53 mutation
Zeng, D., Hu, Z., Yi, Y., Valeria, B., Shan, G., Chen, Z., Zhan, C., Lin, M., Lin, Z., & Wang, Q. (2021) · Figshare · doi:10.6084/m9.figshare.16786906
Neuroimmune Mechanisms in Traumatic Brain Injury and Cancer: Parallel Courses or Existence in Different Orbits
Zhukova, М. А., Ermakova, N. N., Pan, E. S., & Skurikhin, Е. G. (2026) · Biomedicines · doi:10.3390/biomedicines14010112
Mitochondrial metabolic remodeling predicts therapeutic response to PegIFN-α in chronic hepatitis B
Zhang, Y., Han, X., Xu, C., Song, Y., Zhu, J., Zhou, R., Chen, Y., Liu, M., Xu, J., Wu, X., et al. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1719456
Transcriptional and Epigenetic Regulation of T Cell States in Cancer
Ma, S., Hargreaves, D. C., & Kaech, S. M. (2026) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061325-042744
Combining metabolic and checkpoint therapy: 1,25-dihydroxyvitamin D₃ enhances the antiviral efficacy of anti-PD-1 in BVDV infection
Li, Y., He, L., Li, P., Chen, R., Li, F., Yang, L., Zhou, Y., Zhang, Z., Liu, S., Zhao, J., et al. (2026) · Veterinary Microbiology · doi:10.1016/j.vetmic.2026.110950
Dual roles of immunosenescence in cancer immunotherapy
Yu, Y., Sun, L., & Fan, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1779141
Viscoelasticity reprograms T cell metabolism for TCR-T cell manufacturing and therapyPreprint
Li, S., Yang, Y., Li, Y.-R., Liu, Z., Zhou, H., Zhu, Y., Shen, X., Lai, D., Cen, Y., Miller, E., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-8855735/v1
Bioenergetic Profiling of Lymphocytes in Patients With Visceral Leishmaniasis ( VL ) and Post Kala‐Azar Dermal Leishmaniasis ( PKDL )
Sengupta, S., & Chatterjee, M. (2026) · Parasite Immunology · doi:10.1111/pim.70069
Metabolic Constraints and Interactions Drive T-cell Function and Exhaustion in Cancer Progression
Tzeng, S., & Tsai, C.-H. (2026) · Journal of Medical Sciences · doi:10.4103/jmedsci.jmedsci_234_25
Oxygen Delivery Reprograms Hypoxic Tumor Niche to Rejuvenate CAR-NKT Cells for Improved Cancer ImmunotherapyPreprint
Li, S., Shiekh, P. A., Li, Y.-R., Nan, H., Yang, L., Mitchell, K., Yang, Y., & Zhu, Y. (2026) · Research Square · doi:10.21203/rs.3.rs-8296891/v1
Mitochondria and resistance to immunotherapy
Adhikary, K., Chakraborty, A., Chatterjee, S., Ganguly, K., & Maiti, R. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-40535-8.00008-9
Translating IL-2/anti-IL-2 antibody complexes treatment for human tumor immunotherapy
Caudana, P. (2018) · theses.fr (ABES) · doi:10.70675/8a93b17bz416az4e49z9a3bz92c1c8a4cf8c
Integrative analysis of CD8 T-cell responses in the context of adaptive immunity to acute Hepatitis C virus infection
Wolski, D. (2017) · theses.fr (ABES) · doi:10.70675/9fcea3ffz21a8z4dbez9129z3cb7a35425ff
Expression de récepteurs inhibiteurs sur les lymphocytes T infiltrant les tumeurs du rein : signification biologique et clinique
Granier, C. (2018) · theses.fr (ABES) · doi:10.70675/c9815ca0z16eez4d7fz99c8za682491a1112
Rôle de la Neuropiline-1 dans les fonctions effectrices des lymphocytes T CD8 antitumoraux
Leclerc, M. (2018) · theses.fr (ABES) · doi:10.70675/13aee211zad7bz4b07z9a5fz29b15750d99c
Pharmacologic DPP-4 inhibition promotes CD8⁺ T cell metabolic fitness to enhance anti-tumor activityPreprint
Pumar, O. T., VanNoy, E. L., Haffey, A., Gannamedi, D. P., Rafie, C. I., Harwood, D. S. L., Benedetti, J. R., Ballard, C. A. P., Ciervo, E., Coroa, P. H. A. T., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.03.31.715681
Self-citation
Défauts fonctionnels des cellules NK en contexte de stimulation chronique
Marotel, M. (2019) · theses.fr (ABES) · doi:10.70675/1dcb97a5za482z4664zaaf6z62a53817eea9
Régulation métabolique de l'infection des cellules T CD4 par VIH-1 : vers de nouvelles cibles thérapeutiques
Vahlas, Z. (2020) · theses.fr (ABES) · doi:10.70675/c19636d1z1197z46d5z8c67z80971b27db3b
Insights into the physiology of the gamma-delta T Physiologie des lymphocytes T gamma-delta dans l'interaction du cytomégalovirus avec son hôte immunodéprimé
Kaminski, H. (2020) · theses.fr (ABES) · doi:10.70675/7abc23bbz0f82z4a71z9ef9z1bc18c6a14a8
Role of co-activating receptors CD226 and CD137 in T cell exhaustion
Pichler, A. (2020) · theses.fr (ABES) · doi:10.70675/ec9fb2bazf7a9z4305z9a58zb5cbc6e74e63
Immunothérapie et infection VIH-1 : étude préclinique dans un modèle de souris humanisée pour le système immunitaire
Labarthe, L. (2020) · theses.fr (ABES) · doi:10.70675/8e0a6f66ze74dz497cz89b5z17639f9eff02
Characterization of the Tumor Microenvironment in Chronic Lymphocytic Leukemia by Mass Cytometry : Implications for Immunotherapy
Wierz, M. (2020) · theses.fr (ABES) · doi:10.70675/80454a47z3b6bz4b8bza0c3z684d69f087b3
Contribution des réponses immunitaires adaptatives spécifiques des antigènes tumoraux à l'efficacité clinique de l'immunothérapie par inhibition de l'axe PD-1/PD-L1
Balança, C.-C. (2021) · theses.fr (ABES) · doi:10.70675/35353ecez3292z48f1z81ecz10edb0a3d321
The anti-tumoral effects of a low protein diet and of the IRE1α signaling
Turtos, A. M. (2022) · theses.fr (ABES) · doi:10.70675/fd90a3e8ze35az42fdzbd0ez966f12ddad22

Authors: Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E., McLane, L. M., Paley, M. A., Delgoffe, G. M., & Wherry, E. J.
Affiliations: University of Pennsylvania (US)
UPMC Hillman Cancer Center (US)
Corresponding author: Wherry, E. John
ORCID: Bengsch, Bertram
Kurachi, Makoto
Odorizzi, Pamela M.
Pauken, Kristen E.
Attanasio, John
Stelekati, Erietta
Paley, Michael A.
Delgoffe, Greg M.
Wherry, E. John
Venue: Immunity
Publisher: Elsevier BV
Published: 2016-08
Volume: 45
Issue: 2
Pages: 358-373
ISSN: 1074-7613 (ISSN-L)
DOI: 10.1016/j.immuni.2016.07.008
PMC: PMC4988919
OpenAlex: W2478467838
Cited by: 868
References: 40
Citations by year: 2026: 127 · 2025: 87 · 2024: 93 · 2023: 89 · 2022: 92 · 2021: 107 · 2020: 85 · 2019: 63 · 2018: 59 · 2017: 55 · 2016: 10
FWCI: 33.62
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 380 d)
Locations: Immunity (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Cancer Institute (P50CA121973, P50CA097190)
National Institute of Allergy and Infectious Diseases (R01AI115712, R01AI105343, P01AI112521, R21AI117718, U01AI095608, U19AI082630, P01AI108545)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: PD-1, CD8+ T cell exhaustion, glycolysis, mitochondrial metabolism, PGC-1α, mTOR signaling, glucose uptake, chronic viral infection, lymphocytic choriomeningitis virus, PD-L1 blockade, immune checkpoint blockade
MeSH terms: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, Animals, Cells, Cultured, Energy Metabolism, Glucose, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Signal Transduction, Cellular Senescence, Mice, Knockout, CD8-Positive T-Lymphocytes, Mice, Antibodies, Neutralizing, TOR Serine-Threonine Kinases, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Cellular Reprogramming

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8 + T Cell Exhaustion

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Self-check

Citations

Cites

Cited by

Related

Metadata

Record

About these checks