T cell adaptation in chronic infections and tumors

T cell adaptation in chronic infections and tumors

  • IHME Pathogen Core Group. Global burden associated with 85 pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Infect Dis. 2024;24:868–95.

  • GBD 2023 Cancer Collaborators. The global, regional, and national burden of cancer, 1990-2023, with forecasts to 2050: a systematic analysis for the Global Burden of Disease Study 2023. Lancet. 2025;406:1565–86.

    Article 

    Google Scholar
     

  • Delves PJ, Roitt IM. The immune system. First of two parts. N Engl J Med. 2000;343:37–49.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. 2000;343:108–17.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McLane LM, Abdel-Hakeem MS, Wherry EJ. CD8 T cell exhaustion during chronic viral infection and cancer. Annu Rev Immunol. 2019;37:457–95.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun L, Su Y, Jiao A, Wang X, Zhang B. T cells in health and disease. Signal Transduct Target Ther. 2023;8:235.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat Immunol. 2011;12:509–17.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zehn D, King C, Bevan MJ, Palmer E. TCR signaling requirements for activating T cells and for generating memory. Cell Mol Life Sci. 2012;69:1565–75.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossjohn J, Gras S, Miles JJ, Turner SJ, Godfrey DI, McCluskey J. T cell antigen receptor recognition of antigen-presenting molecules. Annu Rev Immunol. 2015;33:169–200.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bakdash G, Sittig SP, van Dijk T, Figdor CG, De Vries IJM. The nature of activatory and tolerogenic dendritic cell-derived signal II. Front Immunol. 2013;4:53.

    Article 
    PubMed 

    Google Scholar
     

  • Valenzuela J, Schmidt C, Mescher M. The roles of IL-12 in providing a third signal for clonal expansion of naive CD8 T cells. J Immunol. 2002;169:6842–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Curtsinger JM, Mescher MF. Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 2010;22:333–40.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Harty JT, Tvinnereim AR, White DW. CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol. 2000;18:275–308.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Samji T, Khanna KM. Understanding memory CD8+ T cells. Immunol Lett. 2017;185:32–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Martin MD, Badovinac VP. Defining memory CD8 T Cell. Front Immunol. 2018. https://doi.org/10.3389/fimmu.2018.02692.

  • Buggert M, Price DA, Mackay LK, Betts MR. Human circulating and tissue-resident memory CD8+ T cells. Nat Immunol. 2023;24:1076–86.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gattinoni L, Speiser DE, Lichterfeld M, Bonini C. T memory stem cells in health and disease. Nat Med. 2017;23:18–27.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Speiser DE, Utzschneider DT, Oberle SG, Münz C, Romero P, Zehn D. T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion? Nat Rev Immunol. 2014;14:768–74.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hsiung S, Egawa T. Population dynamics and gene regulation of T cells in response to chronic antigen stimulation. Int Immunol. 2023;35:67–77.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, et al. Defining ‘T cell exhaustion. Nat Rev Immunol. 2019;19:665–74.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cornberg M, Kenney LL, Chen AT, Waggoner SN, Kim S-K, Dienes HP, et al. Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response. Front Immunol. 2013;4:475.

    Article 
    PubMed 

    Google Scholar
     

  • Giles JR, Ngiow SF, Manne S, Baxter AE, Khan O, Wang P, et al. Shared and distinct biological circuits in effector, memory and exhausted CD8+ T cells revealed by temporal single-cell transcriptomics and epigenetics. Nat Immunol. 2022;23:1600–13.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • McManus DT, Valanparambil RM, Medina CB, Scharer CD, McGuire DJ, Sobierajska E, et al. An early precursor CD8+ T cell that adapts to acute or chronic viral infection. Nature. 2025;640:772–81.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chu T, Wu M, Hoellbacher B, de Almeida GP, Wurmser C, Berner J, et al. Precursors of exhausted T cells are preemptively formed in acute infection. Nature. 2025;640:782–92.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. J Exp Med. 1998;188:2205–13.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gallimore A, Glithero A, Godkin A, Tissot AC, Plückthun A, Elliott T, et al. Induction and exhaustion of lymphocytic choriomeningitis virus-specific cytotoxic T lymphocytes visualized using soluble tetrameric major histocompatibility complex class I-peptide complexes. J Exp Med. 1998;187:1383–93.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bengsch B, Seigel B, Ruhl M, Timm J, Kuntz M, Blum HE, et al. Coexpression of PD-1, 2B4, CD160 and KLRG1 on exhausted HCV-specific CD8+ T cells is linked to antigen recognition and T cell differentiation. PLoS Pathog. 2010;6:e1000947.

    Article 
    PubMed 

    Google Scholar
     

  • Wang S, Zhang Q, Hui H, Agrawal K, Karris MAY, Rana TM. An atlas of immune cell exhaustion in HIV-infected individuals revealed by single-cell transcriptomics. Emerg Microbes Infect. 2020;9:2333–47.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bengsch B, Ohtani T, Khan O, Setty M, Manne S, O’Brien S, et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity. 2018;48:1029–45.e5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Oliveira G, Stromhaug K, Klaeger S, Kula T, Frederick DT, Le PM, et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature. 2021;596:119–25.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Caushi JX, Zhang J, Ji Z, Vaghasia A, Zhang B, Hsiue EH-C, et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature. 2021;596:126–32.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hargreaves RG, Borthwick NJ, Gilardini Montani MS, Piccolella E, Carmichael P, Lechler RI, et al. Dissociation of T cell anergy from apoptosis by blockade of Fas/Apo-1 (CD95) signaling. J Immunol. 1997;158:3099–107.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Frauwirth KA, Alegre ML, Thompson CB. Induction of T cell anergy in the absence of CTLA-4/B7 interaction. J Immunol. 2000;164:2987–93.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tedeschi V, Paldino G, Kunkl M, Paroli M, Sorrentino R, Tuosto L, et al. CD8+ T cell senescence: lights and shadows in viral infections, autoimmune disorders and cancer. Int J Mol Sci. 2022;23:3374.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hou B, Hu Y, Zhu Y, Wang X, Li W, Tang J, et al. SHP-1 Regulates CD8+ T cell effector function but plays a subtle role with SHP-2 in T cell exhaustion due to a stage-specific nonredundant functional relay. J Immunol. 2024;212:397–409.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hui E, Cheung J, Zhu J, Su X, Taylor MJ, Wallweber HA, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355:1428–33.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu X, Dennett P, Zhang J, Sherrard A, Zhao Y, Masubuchi T, et al. CTLA4 depletes T cell endogenous and trogocytosed B7 ligands via cis-endocytosis. J Exp Med. 2023;220:e20221391.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ngiow SF, Manne S, Huang YJ, Azar T, Chen Z, Mathew D, et al. LAG-3 sustains TOX expression and regulates the CD94/NKG2-Qa-1b axis to govern exhausted CD8 T cell NK receptor expression and cytotoxicity. Cell. 2024;187:4336–54.e19.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Andrews LP, Butler SC, Cui J, Cillo AR, Cardello C, Liu C, et al. LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity. Cell. 2024;187:4355–72.e22.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cillo AR, Cardello C, Shan F, Karapetyan L, Kunning S, Sander C, et al. Blockade of LAG-3 and PD-1 leads to coexpression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity. Cell. 2024;187:4373–88.e15.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity. 2016;45:358–73.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015;6:6692.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gupta PK, Godec J, Wolski D, Adland E, Yates K, Pauken KE, et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 2015;11:e1005177.

    Article 
    PubMed 

    Google Scholar
     

  • Vigano S, Alatzoglou D, Irving M, Ménétrier-Caux C, Caux C, Romero P, et al. Targeting adenosine in cancer immunotherapy to enhance T-cell function. Front Immunol. 2019;10:925.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scott AC, Dündar F, Zumbo P, Chandran SS, Klebanoff CA, Shakiba M, et al. TOX is a critical regulator of tumor-specific T cell differentiation. Nature. 2019;571:270–4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE, Roelli P, et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature. 2019;571:265–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature. 2019;571:211–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yao C, Sun H-W, Lacey NE, Ji Y, Moseman EA, Shih H-Y, et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat Immunol. 2019;20:890–901.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bending D, Zikherman J. Nr4a nuclear receptors: markers and modulators of antigen receptor signaling. Curr Opin Immunol. 2023;81:102285.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seo H, Chen J, González-Avalos E, Samaniego-Castruita D, Das A, Wang YH, et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc Natl Acad Sci USA. 2019;116:12410–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang YJ, Ngiow SF, Baxter AE, Manne S, Park SL, Wu JE, et al. Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate. Sci Immunol. 2025;10:eado3032.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Martinez GJ, Pereira RM, Äijö T, Kim EY, Marangoni F, Pipkin ME, et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity. 2015;42:265–78.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hensel, Gu N, Sagar null Z, Wieland D, Jechow K, Kemming J, et al. Memory-like HCV-specific CD8+ T cells retain a molecular scar after cure of chronic HCV infection. Nat Immunol. 2021;22:229–39.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yates KB, Tonnerre P, Martin GE, Gerdemann U, Al Abosy R, Comstock DE, et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat Immunol. 2021;22:1020–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tonnerre P, Wolski D, Subudhi S, Aljabban J, Hoogeveen RC, Damasio M, et al. Differentiation of exhausted CD8+ T cells after termination of chronic antigen stimulation stops short of achieving functional T cell memory. Nat Immunol. 2021;22:1030–41.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abdel-Hakeem MS, Manne S, Beltra J-C, Stelekati E, Chen Z, Nzingha K, et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol. 2021;22:1008–19.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang H, Baxter AE, Zhang Z, Good CR, Alexander KA, Chen Z, et al. Deciphering the role of histone modifications in memory and exhausted CD8 T cells. Sci Rep. 2025;15:17359.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Beltra J-C, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity. 2020;52:825–41.e8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Giles JR, Manne S, Freilich E, Oldridge DA, Baxter AE, George S, et al. Human epigenetic and transcriptional T cell differentiation atlas for identifying functional T cell-specific enhancers. Immunity. 2022;55:557–74.e7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Utzschneider DT, Charmoy M, Chennupati V, Pousse L, Ferreira DP, Calderon-Copete S, et al. T cell factor 1-expressing memory-like CD8(+) T cells sustain the immune response to chronic viral infections. Immunity. 2016;45:415–27.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV, Barnett BE, et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science. 2012;338:1220–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tsui C, Kretschmer L, Rapelius S, Gabriel SS, Chisanga D, Knöpper K, et al. MYB orchestrates T cell exhaustion and response to checkpoint inhibition. Nature. 2022;609:354–60.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen Z, Ji Z, Ngiow SF, Manne S, Cai Z, Huang AC, et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity. 2019;51:840–55.e5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537:417–21.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • He R, Hou S, Liu C, Zhang A, Bai Q, Han M, et al. Follicular CXCR5-expressing CD8(+) T cells curtail chronic viral infection. Nature. 2016;537:412–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Doering TA, Crawford A, Angelosanto JM, Paley MA, Ziegler CG, Wherry EJ. Network analysis reveals centrally connected genes and pathways involved in CD8+ T cell exhaustion versus memory. Immunity. 2012;37:1130–44.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shin H, Blackburn SD, Intlekofer AM, Kao C, Angelosanto JM, Reiner SL, et al. A role for the transcriptional repressor Blimp-1 in CD8(+) T cell exhaustion during chronic viral infection. Immunity. 2009;31:309–20.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hashimoto M, Araki K, Cardenas MA, Li P, Jadhav RR, Kissick HT, et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature. 2022;610:173–81.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Codarri Deak L, Nicolini V, Hashimoto M, Karagianni M, Schwalie PC, Lauener L, et al. PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells. Nature. 2022;610:161–72.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Beltra J-C, Abdel-Hakeem MS, Manne S, Zhang Z, Huang H, Kurachi M, et al. Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure. Immunity. 2023;56:2699–718.e11.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen Y, Zander RA, Wu X, Schauder DM, Kasmani MY, Shen J, et al. BATF regulates progenitor to cytolytic effector CD8+ T cell transition during chronic viral infection. Nat Immunol. 2021;22:996–1007.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seo H, González-Avalos E, Zhang W, Ramchandani P, Yang C, Lio C-WJ, et al. BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nat Immunol. 2021;22:983–95.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sedaghat AR, German J, Teslovich TM, Cofrancesco J, Jie CC, Talbot CC, et al. Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics. J Virol. 2008;82:1870–83.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rallón N, García M, García-Samaniego J, Cabello A, Álvarez B, Restrepo C, et al. Expression of PD-1 and Tim-3 markers of T-cell exhaustion is associated with CD4 dynamics during the course of untreated and treated HIV infection. PLoS One. 2018;13:e0193829.

    Article 
    PubMed 

    Google Scholar
     

  • Fenwick C, Joo V, Jacquier P, Noto A, Banga R, Perreau M, et al. T-cell exhaustion in HIV infection. Immunol Rev. 2019;292:149–63.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jensen SS, Fomsgaard A, Larsen TK, Tingstedt JL, Gerstoft J, Kronborg G, et al. Initiation of antiretroviral therapy (ART) at different stages of HIV-1 disease is not associated with the proportion of exhausted CD8+ T cells. PLoS ONE. 2015;10:e0139573.

    Article 
    PubMed 

    Google Scholar
     

  • Sen DR, Kaminski J, Barnitz RA, Kurachi M, Gerdemann U, Yates KB, et al. The epigenetic landscape of T cell exhaustion. Science. 2016;354:1165–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buggert M, Tauriainen J, Yamamoto T, Frederiksen J, Ivarsson MA, Michaëlsson J, et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog. 2014;10:e1004251.

    Article 
    PubMed 

    Google Scholar
     

  • Veiga-Parga T, Sehrawat S, Rouse BT. Role of regulatory T cells during virus infection. Immunol Rev. 2013;255:182–96.

    Article 
    PubMed 

    Google Scholar
     

  • Patel SV, Jayaweera DT, Althoff KN, Eron JJ, Radtchenko J, Mills A, et al. Real-world efficacy of direct acting antiviral therapies in patients with HIV/HCV. PLoS ONE. 2020;15:e0228847.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Carrat F, Fontaine H, Dorival C, Simony M, Diallo A, Hezode C, et al. Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study. Lancet. 2019;393:1453–64.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shin E-C, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel P-M, et al. Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection. J Clin Invest. 2006;116:3006–14.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heim MH, Thimme R. Innate and adaptive immune responses in HCV infections. J Hepatol. 2014;61:S14–25.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hofmann M, Tauber C, Hensel N, Thimme R. CD8+ T cell responses during HCV infection and HCC. J Clin Med. 2021;10:991.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wolski D, Foote PK, Chen DY, Lewis-Ximenez LL, Fauvelle C, Aneja J, et al. Early transcriptional divergence marks virus-specific primary human CD8+ T cells in chronic versus acute infection. Immunity. 2017;47:648–63.e8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kurktschiev PD, Raziorrouh B, Schraut W, Backmund M, Wächtler M, Wendtner C-M, et al. Dysfunctional CD8+ T cells in hepatitis B and C are characterized by a lack of antigen-specific T-bet induction. J Exp Med. 2014;211:2047–59.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wieland D, Kemming J, Schuch A, Emmerich F, Knolle P, Neumann-Haefelin C, et al. TCF1+ hepatitis C virus-specific CD8+ T cells are maintained after cessation of chronic antigen stimulation. Nat Commun. 2017;8:15050.

    Article 
    PubMed 

    Google Scholar
     

  • Salimi Alizei E, Hofmann M, Thimme R, Neumann-Haefelin C. Mutational escape from cellular immunity in viral hepatitis: variations on a theme. Curr Opin Virol. 2021;50:110–8.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wieland S, Thimme R, Purcell RH, Chisari FV. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci USA. 2004;101:6669–74.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Thimme R, Hofmann M, Bertoletti A, Le Bert N. Decoding HBV-specific adaptive immunity: from natural clearance to cure. Gut. 2025;gutjnl-2025-337129. https://doi.org/10.1136/gutjnl-2025-337129. Epub ahead of print.

  • Thimme R, Bertoletti A, Iannacone M. Beyond exhaustion: the unique characteristics of CD8+ T cell dysfunction in chronic HBV infection. Nat Rev Immunol. 2024;24:775–6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bengsch B, Martin B, Thimme R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J Hepatol. 2014;61:1212–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schuch A, Salimi Alizei E, Heim K, Wieland D, Kiraithe MM, Kemming J, et al. Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load. Gut. 2019;68:905–15.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hoogeveen RC, Robidoux MP, Schwarz T, Heydmann L, Cheney JA, Kvistad D, et al. Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection. Gut. 2019;68:893–904.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heim, Binder K, Sagar null B, Wieland D, Hensel N, Llewellyn-Lacey S, et al. TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection. Gut. 2020;70:1550–60.

    Article 
    PubMed 

    Google Scholar
     

  • Winkler F, Hipp AV, Ramirez C, Martin B, Villa M, Neuwirt E, et al. Enolase represents a metabolic checkpoint controlling the differential exhaustion programmes of hepatitis virus-specific CD8+ T cells. Gut. 2023;72:1971–84.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pallett LJ, Gill US, Quaglia A, Sinclair LV, Jover-Cobos M, Schurich A, et al. Metabolic regulation of hepatitis B immunopathology by myeloid-derived suppressor cells. Nat Med. 2015;21:591–600.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, Ganzer L, et al. Immunosurveillance of the liver by intravascular effector CD8(+) T cells. Cell. 2015;161:486–500.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fisicaro P, Barili V, Montanini B, Acerbi G, Ferracin M, Guerrieri F, et al. Targeting mitochondrial dysfunction can restore antiviral activity of exhausted HBV-specific CD8 T cells in chronic hepatitis B. Nat Med. 2017;23:327–36.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Venzin V, Beccaria CG, Perucchini C, Delfino P, Bono EB, Giustini L, et al. CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming. Nat Immunol. 2025;26:1352–66.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Andreata F, Laura C, Ravà M, Krueger CC, Ficht X, Kawashima K, et al. Therapeutic potential of cosignaling receptor modulation in hepatitis B. Cell. 2024;187:4078–94.e21.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Andreata F, Moynihan KD, Fumagalli V, Di Lucia P, Pappas DC, Kawashima K, et al. CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus. Sci Transl Med. 2024;16:eadi1572.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bosch M, Kallin N, Donakonda S, Zhang JD, Wintersteller H, Hegenbarth S, et al. A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection. Nature. 2024;631:867–75.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heim, Sagar null K, Sogukpinar Ö, Llewellyn-Lacey S, Price DA, Emmerich F, et al. Attenuated effector T cells are linked to control of chronic HBV infection. Nat Immunol. 2024;25:1650–62.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumor development and shape tumor immunogenicity. Nature. 2001;410:1107–11.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gubin MM, Vesely MD. Cancer Immunoediting in the Era of Immuno-oncology. Clin Cancer Res. 2022;28:3917–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases-elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16–25.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004;21:137–48.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30:R921–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nagasaki J, Togashi Y. A variety of ‘exhausted’ T cells in the tumor microenvironment. Int Immunol. 2022;34:563–70.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Verdegaal EME, de Miranda NFCC, Visser M, Harryvan T, van Buuren MM, Andersen RS, et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature. 2016;536:91–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Finn OJ. Cancer immunology. N Engl J Med. 2008;358:2704–15.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scanlan MJ, Gure AO, Jungbluth AA, Old LJ, Chen Y-T. Cancer/testis antigens: an expanding family of targets for cancer immunotherapy. Immunol Rev. 2002;188:22–32.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Disis ML, Bernhard H, Jaffee EM. Use of tumor-responsive T cells as cancer treatment. Lancet. 2009;373:673–83.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huber F, Bassani-Sternberg M. Defects in antigen processing and presentation: mechanisms, immune evasion and implications for cancer vaccine development. Nat Rev Immunol. 2025. https://doi.org/10.1038/s41577-025-01208-8.

    Article 
    PubMed 

    Google Scholar
     

  • Al Bakir M, Reading JL, Gamble S, Rosenthal R, Uddin I, Rowan A, et al. Clonal driver neoantigen loss under EGFR TKI and immune selection pressures. Nature. 2025;639:1052–9.

    Article 
    PubMed 

    Google Scholar
     

  • Iwahori K. Cytotoxic CD8+ lymphocytes in the tumor microenvironment. Adv Exp Med Biol. 2020;1224:53–62.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mahmoud SMA, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AHS, et al. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.

    Article 
    PubMed 

    Google Scholar
     

  • Kawai O, Ishii G, Kubota K, Murata Y, Naito Y, Mizuno T, et al. Predominant infiltration of macrophages and CD8(+) T Cells in cancer nests is a significant predictor of survival in stage IV non-small cell lung cancer. Cancer. 2008;113:1387–95.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58:3491–4.

    CAS 
    PubMed 

    Google Scholar
     

  • Philip M, Schietinger A. CD8+ T cell differentiation and dysfunction in cancer. Nat Rev Immunol. 2022;22:209–23.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Corgnac S, Boutet M, Kfoury M, Naltet C, Mami-Chouaib F. The emerging role of CD8+ tissue resident memory T (TRM) cells in antitumor immunity: a unique functional contribution of the CD103 integrin. Front Immunol. 2018;9:1904.

    Article 
    PubMed 

    Google Scholar
     

  • Zhang N, Bevan MJ. Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity. 2013;39:687–96.

    Article 
    PubMed 

    Google Scholar
     

  • Boutet M, Gauthier L, Leclerc M, Gros G, de Montpreville V, Théret N, et al. TGFβ signaling intersects with CD103 integrin signaling to promote T-lymphocyte accumulation and antitumor activity in the lung tumor microenvironment. Cancer Res. 2016;76:1757–69.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Desbois M, Udyavar AR, Ryner L, Kozlowski C, Guan Y, Dürrbaum M, et al. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat Commun. 2020;11:5583.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saadey AA, Yousif A, Osborne N, Shahinfar R, Chen Y-L, Laster B, et al. Rebalancing TGFβ1/BMP signals in exhausted T cells unlocks responsiveness to immune checkpoint blockade therapy. Nat Immunol. 2023;24:280–94.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, Bartholin L, et al. TGF-β: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst. 2014;106:djt369.

    Article 
    PubMed 

    Google Scholar
     

  • Beumer-Chuwonpad A, van Alphen FPJ, Kragten NAM, Freen-van Heeren JJ, Rodriguez Gomez M, Verhoeven AJ, et al. Memory CD8+ T cells upregulate glycolysis and effector functions under limiting oxygen conditions. Eur J Immunol. 2023;53:e2249918.

    Article 
    PubMed 

    Google Scholar
     

  • Reina-Campos M, Heeg M, Kennewick K, Mathews IT, Galletti G, Luna V, et al. Metabolic programs of T cell tissue residency empower tumor immunity. Nature. 2023;621:179–87.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Elia I, Rowe JH, Johnson S, Joshi S, Notarangelo G, Kurmi K, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab. 2022;34:1137–50.e6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Okła K, Farber DL, Zou W. Tissue-resident memory T cells in tumor immunity and immunotherapy. J Exp Med. 2021;218:e20201605.

    Article 
    PubMed 

    Google Scholar
     

  • Damei I, Trickovic T, Mami-Chouaib F, Corgnac S. Tumor-resident memory T cells as a biomarker of the response to cancer immunotherapy. Front Immunol. 2023;14:1205984.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kok L, Dijkgraaf FE, Urbanus J, Bresser K, Vredevoogd DW, Cardoso RF, et al. A committed tissue-resident memory T cell precursor within the circulating CD8+ effector T cell pool. J Exp Med. 2020;217:e20191711.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kok L, Masopust D, Schumacher TN. The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol. 2022;22:283–93.

    Article 
    CAS 

    Google Scholar
     

  • Rosato PC, Wijeyesinghe S, Stolley JM, Nelson CE, Davis RL, Manlove LS, et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat Commun. 2019;10:567.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meier SL, Satpathy AT, Wells DK. Bystander T cells in cancer immunology and therapy. Nat Cancer. 2022;3:143–55.

    Article 
    PubMed 

    Google Scholar
     

  • Leem G, Jeon M, Kim KW, Jeong S, Choi SJ, Lee YJ, et al. Tumor-infiltrating bystander CD8+ T cells activated by IL-15 contribute to tumor control in non-small cell lung cancer. Thorax. 2022;77:769–80.

    Article 

    Google Scholar
     

  • Schenk TJC, Vos M, van Sleen Y, Hoeboer J, van Baarle D, Guichelaar T. IL-2 mediates human bystander CD8+ T-cell responses to innate immune signals. J Immunol. 2025;214:3399–412.

  • Li L, Jay SM, Wang Y, Wu S, Xiao W. Z. IL-12 stimulates CTLs to secrete exosomes capable of activating bystander CD8+ T cells. Sci Rep. 2017;7:13365.

    Article 
    PubMed 

    Google Scholar
     

  • Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest. 2008;118:1398–404.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Simoni Y, Becht E, Fehlings M, Loh CY, Koo S-L, Teng KWW, et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumor infiltrates. Nature. 2018;557:575–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shah DD, Chorawala MR, Raghani NR, Patel R, Fareed M, Kashid VA, et al. Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies. Med Oncol. 2025;42:117.

    Article 
    PubMed 

    Google Scholar
     

  • de Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41:374–403.

    Article 
    PubMed 

    Google Scholar
     

  • Li R, Mukherjee MB, Lin J. Coordinated regulation of myeloid-derived suppressor cells by cytokines and chemokines. Cancers. 2022;14:1236.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu L, Li Y, Li B. Interactions between cancer cells and tumor-associated macrophages in tumor microenvironment. Biochim Biophys Acta Rev Cancer. 2025;1880:189344.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mimura K, Teh JL, Okayama H, Shiraishi K, Kua L-F, Koh V, et al. PD-L1 expression is mainly regulated by interferon gamma associated with JAK-STAT pathway in gastric cancer. Cancer Sci. 2018;109:43–53.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li Y-M, Yu J-M, Liu Z-Y, Yang H-J, Tang J, Chen Z-N. Programmed death ligand 1 indicates pre-existing adaptive immune response by tumor-infiltrating CD8+ T cells in non-small cell lung cancer. Int J Mol Sci. 2019;20:5138.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang R, Sun L, Li C-F, Wang Y-H, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021;12:832.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Paolini R, Molfetta R. CD155 and its receptors as targets for cancer therapy. Int J Mol Sci. 2023;24:12958.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mohamed AH, Obeid RA, Fadhil AA, Amir AA, Adhab ZH, Jabouri EA, et al. BTLA and HVEM: emerging players in the tumor microenvironment and cancer progression. Cytokine. 2023;172:156412.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • El Sayed R, Haibe Y, Amhaz G, Bouferraa Y, Shamseddine A. Metabolic factors affecting tumor immunogenicity: what is happening at the cellular level? Int J Mol Sci. 2021;22:2142.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41:421–33.

    Article 
    CAS 

    Google Scholar
     

  • Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the tumor microenvironment that influence immune cell functions: hypoxia, oxidative stress, metabolic alterations. Cancers. 2020;12:3802.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Song X, Zhang Y, Zhang L, Song W, Shi L. Hypoxia enhances indoleamine 2,3-dioxygenase production in dendritic cells. Oncotarget. 2018;9:11572–80.

    Article 
    PubMed 

    Google Scholar
     

  • Vaupel P, Multhoff G. Hypoxia-/HIF-1α-driven factors of the tumor microenvironment impeding antitumor immune responses and promoting malignant progression. Adv Exp Med Biol. 2018;1072:171–5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang X, Zhang F, Wang X, Liu K. The role of indoleamine 2,3-dioxygenase 1 in regulating tumor microenvironment. Cancers. 2022;14:2756.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Estephan H, Tailor A, Parker R, Kreamer M, Papandreou I, Campo L, et al. Hypoxia promotes tumor immune evasion by suppressing MHC-I expression and antigen presentation. EMBO J. 2025;44:903–22.

    Article 
    CAS 

    Google Scholar
     

  • Sethumadhavan S, Silva M, Philbrook P, Nguyen T, Hatfield SM, Ohta A, et al. Hypoxia and hypoxia-inducible factor (HIF) downregulate antigen-presenting MHC class I molecules limiting tumor cell recognition by T cells. PLoS ONE. 2017;12:e0187314.

    Article 
    PubMed 

    Google Scholar
     

  • James E, Bailey I, Sugiyarto G, Elliott T. Induction of protective antitumor immunity through attenuation of ERAAP function. J Immunol. 2013;190:5839–46.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peralta RM, Xie B, Lontos K, Nieves-Rosado H, Spahr K, Joshi S, et al. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat Immunol. 2024;25:2297–307.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Xu S, Chaudhary O, Rodríguez-Morales P, Sun X, Chen D, Zappasodi R, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity. 2021;54:1561–77.e7.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Corn KC, Windham MA, Rafat M. Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res. 2020;80:101055.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Silverstein RL, Febbraio M. CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal. 2009;2:re3.

    Article 
    PubMed 

    Google Scholar
     

  • Tagliani E, Guermonprez P, Sepúlveda J, López-Bravo M, Ardavín C, Amigorena S, et al. Selection of an antibody library identifies a pathway to induce immunity by targeting CD36 on steady-state CD8 alpha+ dendritic cells. J Immunol. 2008;180:3201–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Perry JSA, Russler-Germain EV, Zhou YW, Purtha W, Cooper ML, Choi J, et al. Transfer of cell-surface antigens by scavenger receptor CD36 promotes thymic regulatory T cell receptor repertoire development and allo-tolerance. Immunity. 2018;48:923–36.e4.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang H, Franco F, Tsui Y-C, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020;21:298–308.

    Article 

    Google Scholar
     

  • Li S, Zhang Y, Tong H, Sun H, Liao H, Li Q, et al. Metabolic regulation of immunity in the tumor microenvironment. Cell Rep. 2025;44:116463.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang Z, Mandelkow T, Raedler JB, Bady E, Müller JH, Simon R, et al. Prevalence, immune checkpoint expression, and spatial interplay of immune cells are linked to favorable tumor phenotype in 4915 human carcinomas. Lab Invest. 2025;105:104248.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348:74–80.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ouyang P, Zhang J, He X, Yang C, Zeng D, Xu D. Infiltration characteristics and regulatory mechanisms of CD8+ T lymphocytes in solid tumors: spatial distribution, biological functions, and interactions with the immune microenvironment. Front Immunol. 2025;16:1661545.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Simsek H, Klotzsch E. The solid tumor microenvironment-Breaking the barrier for T cells: how the solid tumor microenvironment influences T cells: how the solid tumor microenvironment influences T cells. Bioessays. 2022;44:e2100285.

    Article 
    PubMed 

    Google Scholar
     

  • Wang T, Song W, Tang Y, Yi J, Pan H. Breaking the immune desert: strategies for overcoming the immunological challenges of pancreatic cancer. Biochim Biophys Acta Rev Cancer. 2025;1880:189353.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morrison AH, Byrne KT, Vonderheide RH. Immunotherapy and prevention of pancreatic cancer. Trends Cancer. 2018;4:418–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Imamura T, Ashida R, Ohshima K, Uesaka K, Sugiura T, Ohgi K, et al. Characterization of pancreatic cancer with ultralow tumor mutational burden. Sci Rep. 2023;13:4359.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo J, Wang S, Gao Q. An integrated overview of the immunosuppression features in the tumor microenvironment of pancreatic cancer. Front Immunol. 2023;14:1258538.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Seo YD, Pillarisetty VG. T-cell programming in pancreatic adenocarcinoma: a review. Cancer Gene Ther. 2017;24:106–13.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Saka D, Gökalp M, Piyade B, Cevik NC, Arik Sever E, Unutmaz D, et al. Mechanisms of T-cell exhaustion in pancreatic cancer. Cancers. 2020;12:2274.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Alturki NA. Review of the immune checkpoint inhibitors in the context of cancer treatment. J Clin Med. 2023;12:4301.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Im A, Pavletic SZ. Immunotherapy in hematologic malignancies: past, present, and future. J Hematol Oncol. 2017;10:94.

    Article 
    PubMed 

    Google Scholar
     

  • Nixon NA, Blais N, Ernst S, Kollmannsberger C, Bebb G, Butler M, et al. Current landscape of immunotherapy in the treatment of solid tumors, with future opportunities and challenges. Curr Oncol. 2018;25:e373–84.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234:8509–21.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S, Pais Ferreira D, et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity. 2019;50:195–.e10.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Connolly KA, Kuchroo M, Venkat A, Khatun A, Wang J, William I, et al. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci Immunol. 2021;6:eabg7836.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schenkel JM, Herbst RH, Canner D, Li A, Hillman M, Shanahan S-L, et al. Conventional type I dendritic cells maintain a reservoir of proliferative tumor-antigen specific TCF-1+ CD8+ T cells in tumor-draining lymph nodes. Immunity. 2021;54:2338–53.e6.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lugli E, Galletti G, Boi SK, Youngblood BA. Stem, effector, and hybrid states of memory CD8+ T cells. Trends Immunol. 2020;41:17–28.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fransen MF, Schoonderwoerd M, Knopf P, Camps MG, Hawinkels LJ, Kneilling M, et al. Tumor-draining lymph nodes are pivotal in PD-1/PD-L1 checkpoint therapy. JCI Insight. 2018;3:e124507–124507.

    Article 
    PubMed 

    Google Scholar
     

  • Chow MT, Ozga AJ, Servis RL, Frederick DT, Lo JA, Fisher DE, et al. Intratumoral activity of the CXCR3 chemokine system is required for the efficacy of anti-PD-1 therapy. Immunity. 2019;50:1498–512.e5.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–29.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fountzilas E, Kurzrock R, Vo HH, Tsimberidou A-M. Wedding of molecular alterations and immune checkpoint blockade: genomics as a matchmaker. J Natl Cancer Inst. 2021;113:1634–47.

    Article 
    PubMed 

    Google Scholar
     

  • Lauss M, Phung B, Borch TH, Harbst K, Kaminska K, Ebbesson A, et al. Molecular patterns of resistance to immune checkpoint blockade in melanoma. Nat Commun. 2024;15:3075.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wang X, He J, Ding G, Tang Y, Wang Q. Overcoming resistance to PD-1 and CTLA-4 blockade mechanisms and therapeutic strategies. Front Immunol. 2025;16:1688699.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bell HN, Zou W. Beyond the barrier: unraveling the mechanisms of immunotherapy resistance. Annu Rev Immunol. 2024;42:521–50.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Qin A, Lima F, Bell S, Kalemkerian GP, Schneider BJ, Ramnath N, et al. Cellular engagement and interaction in the tumor microenvironment predict nonresponse to PD-1/PD-L1 inhibitors in metastatic non-small cell lung cancer. Sci Rep. 2022;12:9054.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Davar D, Anderson AC, Diaz-Padilla I. Therapeutic potential of targeting LAG-3 in cancer. J Immunother Cancer. 2025;13:e011652.

    Article 
    PubMed 

    Google Scholar
     

  • Xu Y, He L, Fu Q, Hu J. Metabolic reprogramming in the tumor microenvironment with immunocytes and immune checkpoints. Front Oncol. 2021;11:759015.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jaiswal AR, Liu AJ, Pudakalakatti S, Dutta P, Jayaprakash P, Bartkowiak T, et al. Melanoma evolves complete immunotherapy resistance through the acquisition of a hypermetabolic phenotype. Cancer Immunol Res. 2020;8:1365–80.

    Article 
    PubMed 

    Google Scholar
     

  • Verma S, Budhu S, Serganova I, Dong L, Mangarin LM, Khan JF, et al. Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models. J Clin Invest. 2024;134:e177606.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yun J, Rago C, Cheong I, Pagliarini R, Angenendt P, Rajagopalan H, et al. Glucose deprivation contributes to the development of KRAS pathway mutations in tumor cells. Science. 2009;325:1555–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kilic IB, Weberova P, VanDyke D, Sirova M, Kubesova K, Fabilane CS, et al. Temporal optimization of CD25-biased IL-2 agonists and immune checkpoint blockade leads to synergistic anticancer activity despite robust regulatory T cell expansion. J Immunother Cancer. 2025;13:e010465.

    Article 
    PubMed 

    Google Scholar
     

  • Waldmann TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat Rev Immunol. 2006;6:595–601.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Desbois M, Le Vu P, Coutzac C, Marcheteau E, Béal C, Terme M, et al. IL-15 trans-signaling with the superagonist RLI promotes effector/memory CD8+ T cell responses and enhances antitumor activity of PD-1 antagonists. J Immunol. 2016;197:168–78.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pail O, Lin MJ, Anagnostou T, Brown BD, Brody JD. Cancer vaccines and the future of immunotherapy. Lancet. 2025;406:189–202.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Grippin AJ, Marconi C, Copling S, Li N, Braun C, Woody C, et al. SARS-CoV-2 mRNA vaccines sensitize tumors to immune checkpoint blockade. Nature. 2025;647:488–97.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Guo R, Li J, Hu J, Fu Q, Yan Y, Xu S, et al. Combination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy. Int Immunopharmacol. 2023;120:110417.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu S, Jiang W, Sheng J, Wang L, Cui M. Adoptive cell therapy for cancer: combination strategies and biomarkers. Front Immunol. 2025;16:1603792.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64–73.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chmielewski M, Hombach AA, Abken H. Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptor-redirected T cells. Front Immunol. 2013;4:371.

    Article 
    PubMed 

    Google Scholar
     

  • Kouro T, Himuro H, Sasada T. Exhaustion of CAR T cells: potential causes and solutions. J Transl Med. 2022;20:239.

    Article 
    PubMed 

    Google Scholar
     

  • Zugasti I, Espinosa-Aroca Lady, Fidyt K, Mulens-Arias V, Diaz-Beya M, Juan M, et al. CAR-T cell therapy for cancer: current challenges and future directions. Signal Transduct Target Ther. 2025;10:210.

    Article 
    PubMed 

    Google Scholar
     

  • Sommermeyer D, Hudecek M, Kosasih PL, Gogishvili T, Maloney DG, Turtle CJ, et al. Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia. 2016;30:492–500.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol. 2019;10:128.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lynn RC, Weber EW, Sotillo E, Gennert D, Xu P, Good Z, et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature. 2019;576:293–300.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brudno JN, Maus MV, Hinrichs CS. CAR T cells and T-cell therapies for cancer: a translational science review. JAMA. 2024;332:1924–35.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Getts D, Hofmeister R, Quintás-Cardama A. Synthetic T cell receptor-based lymphocytes for cancer therapy. Adv Drug Deliv Rev. 2019;141:47–54.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rodríguez JA. HLA-mediated tumor escape mechanisms that may impair immunotherapy clinical outcomes via T-cell activation. Oncol Lett. 2017;14:4415–27.

    Article 
    PubMed 

    Google Scholar
     

  • Chandran SS, Klebanoff CA. T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance. Immunol Rev. 2019;290:127–47.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol. 2022;19:775–90.

    Article 
    PubMed 

    Google Scholar
     

  • Kim K, Park S, Park SY, Kim G, Park SM, Cho J-W, et al. Single-cell transcriptome analysis reveals TOX as a promoting factor for T cell exhaustion and a predictor for anti-PD-1 responses in human cancer. Genome Med. 2020;12:22.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li L, Mueller YM, Hioki K, den Dekker RJH, Brouwers-Haspels I, Mezzanotte L, et al. A novel TOX-nanoluciferase reporter mouse for exploring modulators of T cell exhaustion. J Immunol. 2025;214:1398–409.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu X, Wang Y, Lu H, Li J, Yan X, Xiao M, et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature. 2019;567:525–9.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Raman MCC, Rizkallah PJ, Simmons R, Donnellan Z, Dukes J, Bossi G, et al. Direct molecular mimicry enables off-target cardiovascular toxicity by an enhanced affinity TCR designed for cancer immunotherapy. Sci Rep. 2016;6:18851.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Morgan RA, Chinnasamy N, Abate-Daga D, Gros A, Robbins PF, Zheng Z, et al. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J Immunother. 2013;36:133–51.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Haas AR, Golden RJ, Litzky LA, Engels B, Zhao L, Xu F, et al. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol Ther. 2023;31:2309–25.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bijen HM, van der Steen DM, Hagedoorn RS, Wouters AK, Wooldridge L, Falkenburg JHF, et al. Preclinical strategies to identify off-target toxicity of high-affinity TCRs. Mol Ther. 2018;26:1206–14.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kunert A, Obenaus M, Lamers CHJ, Blankenstein T, Debets R. T-cell receptors for clinical therapy: in vitro assessment of toxicity risk. Clin Cancer Res. 2017;23:6012–20.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cameron BJ, Gerry AB, Dukes J, Harper JV, Kannan V, Bianchi FC, et al. Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive target for engineered MAGE A3-directed T cells. Sci Transl Med. 2013;5:197ra103.

    Article 
    PubMed 

    Google Scholar
     

  • Cosenza M, Sacchi S, Pozzi S. Cytokine release syndrome associated with T-cell-based therapies for hematological malignancies: pathophysiology, clinical presentation, and treatment. Int J Mol Sci. 2021;22:7652.

    Article 
    CAS 
    PubMed 

    Google Scholar