Peng K, Fu YX, Liang Y. Engineering cytokines for tumor-targeting and selective T cell activation. Trends Mol Med. 2025;31:373–87.
Google Scholar
Xue D, Hsu E, Fu YX, Peng H. Next-generation cytokines for cancer immunotherapy. Antib Ther. 2021;4:123–33.
Google Scholar
Kureshi CT, Dougan SK. Cytokines in cancer. Cancer Cell. 2025;43:15–35.
Google Scholar
Saxton RA, Glassman CR, Garcia KC. Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov. 2023;22:21–37.
Google Scholar
Leonard WJ, Lin JX. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov. 2023;22:827–54.
Google Scholar
Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022;19:237–53.
Google Scholar
Harris KE, Lorentsen KJ, Malik-Chaudhry HK, Loughlin K, Basappa HM, Hartstein S, et al. A bispecific antibody agonist of the IL-2 heterodimeric receptor preferentially promotes in vivo expansion of CD8 and NK cells. Sci Rep. 2021;11:10592.
Google Scholar
Yen M, Ren J, Liu Q, Glassman CR, Sheahan TP, Picton LK, et al. Facile discovery of surrogate cytokine agonists. Cell. 2022;185:1414–1430 e19.
Google Scholar
Montorfani J, Hatterer E, Chatel L, Lesnier A, Viandier A, Daubeuf B, et al. Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies. J Immunother Cancer. 2025;13:e010650.
Google Scholar
Lipinski B, Unmuth L, Arras P, Endruszeit R, Becker S, Rödel JM, et al. Taming interleukin-12: Engineering of bispecific antibody-based IL-12 mimetics with biased agonism capacities. Protein Sci. 2025;34:e70072.
Google Scholar
Lipinski B, Unmuth L, Arras P, Becker S, Bauer C, Toleikis L, et al. Generation and engineering of potent single domain antibody-based bispecific IL-18 mimetics resistant to IL-18BP decoy receptor inhibition. MAbs. 2023;15:2236265.
Google Scholar
Nan Y, Zhu M, Wang Q, Du X, Xu C, Huang Y, et al. Nanobody-engineered bispecific IL-18 mimetics drive antitumor immunity by engaging CD8(+) T-cell and evading IL-18BP in preclinical models. Mol Ther. 2025;33:4988–5002.
Google Scholar
Trenker R, Rokkam D, Morin A, Balasubrahmanyam P, Paredes V, Cheng I, et al. Structure-Guided Stapling of Dimeric Conformations and Linker Engineering Enhance Thermostability and Fine-Tune Activity of Bispecific VHH Cytokine Agonists. Antibodies. 2025;14:74.
Google Scholar
Miller JS, Morishima C, McNeel DG, Patel MR, Kohrt H, Thompson JA, et al. A First-in-Human Phase I Study of Subcutaneous Outpatient Recombinant Human IL15 (rhIL15) in Adults with Advanced Solid Tumors. Clin Cancer Res. 2018;24:1525–35.
Google Scholar
Wrangle JM, Velcheti V, Patel MR, Garrett-Mayer E, Hill EG, Ravenel JG, et al. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a nonrandomized, open-label, phase 1b trial. Lancet Oncol. 2018;19:694–704.
Google Scholar
Steel JC, Waldmann TA, Morris JC. Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol Sci. 2012;33:35–41.
Google Scholar
Conlon KC, Lugli E, Welles HC, Rosenberg SA, Fojo AT, Morris JC, et al. Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. J Clin Oncol. 2015;33:74–82.
Google Scholar
Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, et al. IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-gamma. J Immunol. 2015;195:2353–64.
Google Scholar
Fehniger TA, Caligiuri MA. Interleukin 15: biology and relevance to human disease. Blood. 2001;97:14–32.
Google Scholar
Conlon KC, Potter EL, Pittaluga S, Lee CR, Miljkovic MD, Fleisher TA, et al. IL15 by Continuous Intravenous Infusion to Adult Patients with Solid Tumors in a Phase I Trial Induced Dramatic NK-Cell Subset Expansion. Clin Cancer Res. 2019;25:4945–54.
Google Scholar
Shen J, Zou Z, Guo J, Cai Y, Xue D, Liang Y, et al. An engineered concealed IL-15-R elicits tumor-specific CD8+T-cell responses through PD-1-cis delivery. J Exp Med, 2022;219:e20220745.
Guo J, Liang Y, Xue D, Shen J, Cai Y, Zhu J, et al. Tumor-conditional IL-15 pro-cytokine reactivates anti-tumor immunity with limited toxicity. Cell Res. 2021;31:1190–8.
Google Scholar
Cai Y, Han Z, Shen J, Zou Z, Guo J, Liang Y, et al. Concurrent intratumoural T(reg) cell depletion and CD8(+) T-cell expansion via a cleavable anti-4-1BB-interleukin-15 fusion protein. Nat Biomed Eng. 2025;9:952–66.
Google Scholar
Raeber ME, Sahin D, Boyman O. Interleukin-2-based therapies in cancer. Sci Transl Med. 2022;14:eabo5409.
Google Scholar
Lv Y, Qi J, Babon JJ, Cao L, Fan G, Lang J, et al. The JAK-STAT pathway: from structural biology to cytokine engineering. Signal Transd Target Ther. 2024;9:221.
Google Scholar
Chen X, Zaro JL, Shen WC. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev. 2013;65:1357–69.
Google Scholar
Ring AM, Lin JX, Feng D, Mitra S, Rickert M, Bowman GR, et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat Immunol. 2012;13:1187–95.
Google Scholar
Silva DA, Yu S, Ulge UY, Spangler JB, Jude KM, Labão-Almeida C, et al. De novo design of potent and selective mimics of IL-2 and IL-15. Nature. 2019;565:186–91.
Google Scholar
Hale G. Living in LALA land? Forty years of attenuating Fc effector functions. Immunol Rev. 2024;328:422–37.
Google Scholar
Chiffelle J, Barras D, Pétremand R, Orcurto A, Bobisse S, Arnaud M, et al. Tumor-reactive T-cell clonotype dynamics underlying clinical response to TIL therapy in melanoma. Immunity. 2024;57:2466–2482 e12.
Google Scholar
Chauvin JM, Ka M, Pagliano O, Menna C, Ding Q, DeBlasio R, et al. IL15 Stimulation with TIGIT Blockade Reverses CD155-mediated NK-Cell Dysfunction in Melanoma. Clin Cancer Res. 2020;26:5520–33.
Google Scholar
Judge SJ, et al., Analysis of tumor-infiltrating NK and T cells highlights IL-15 stimulation and TIGIT blockade as a combination immunotherapy strategy for soft tissue sarcomas. J Immunother Cancer 2020;8:e001355.
Luo B, Sun Y, Zhan Q, Luo Y, Chen Y, Fu T, et al. Combining TIGIT blockade with IL-15 stimulation is a promising immunotherapy strategy for lung adenocarcinoma. Clin Transl Med. 2024;14:e1553.
Google Scholar
Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T-cell immunity. Science. 2008;322:1097–100.
Google Scholar
Chiba K, Yanagawa Y, Masubuchi Y, Kataoka H, Kawaguchi T, Ohtsuki M, et al. FTY720, a novel immunosuppressant, induces sequestration of circulating mature lymphocytes by acceleration of lymphocyte homing in rats. I. FTY720 selectively decreases the number of circulating mature lymphocytes by acceleration of lymphocyte homing. J Immunol. 1998;160:5037–44.
Google Scholar
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science. 2002;296:346–9.
Google Scholar
Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem. 2002;277:21453–7.
Google Scholar
Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature. 2004;427:355–60.
Google Scholar
Lee J, Lee K, Bae H, Lee K, Lee S, Ma J, et al. IL-15 promotes self-renewal of progenitor exhausted CD8 T cells during persistent antigenic stimulation. Front Immunol. 2023;14:1117092.
Google Scholar
Giuffrida L, Sek K, Henderson MA, House IG, Lai J, Chen A, et al. IL-15 Preconditioning Augments CAR T-Cell Responses to Checkpoint Blockade for Improved Treatment of Solid Tumors. Mol Ther. 2020;28:2379–93.
Google Scholar
Alizadeh D, Wong RA, Yang X, Wang D, Pecoraro JR, Kuo CF, et al. IL15 Enhances CAR-T-Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res. 2019;7:759–72.
Google Scholar
Bae J, Liu L, Moore C, Hsu E, Zhang A, Ren Z, et al. IL-2 delivery by engineered mesenchymal stem cells reinvigorates CD8(+) T cells to overcome immunotherapy resistance in cancer. Nat Cell Biol. 2022;24:1754–65.
Google Scholar
Bagchi S, Yuan R, Engleman EG. Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance. Annu Rev Pathol. 2021;16:223–49.
Google Scholar
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359:1350–5.
Google Scholar
Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell. 2021;184:5309–37.
Google Scholar
Kraehenbuehl L, Weng CH, Eghbali S, Wolchok JD, Merghoub T. Enhancing immunotherapy in cancer by targeting emerging immunomodulatory pathways. Nat Rev Clin Oncol. 2022;19:37–50.
Google Scholar
Tang Z, Kang B, Li C, Chen T, Zhang Z. GEPIA2: an enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 2019;47:W556–W560.
Google Scholar
Lipiäinen T, Peltoniemi M, Sarkhel S, Yrjönen T, Vuorela H, Urtti A, et al. Formulation and stability of cytokine therapeutics. J Pharm Sci. 2015;104:307–26.
Google Scholar
Ricci MS, Brems DN. Common structural stability properties of 4-helical bundle cytokines: possible physiological and pharmaceutical consequences. Curr Pharm Des. 2004;10:3901–11.
Google Scholar
Deckers J, Anbergen T, Hokke AM, de Dreu A, Schrijver DP, de Bruin K, et al. Engineering cytokine therapeutics. Nat Rev Bioeng. 2023;1:286–303.
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.
Google Scholar
Ross SH, Cantrell DA. Signaling and Function of Interleukin-2 in T Lymphocytes. Annu Rev Immunol. 2018;36:411–33.
Google Scholar
Abbas AK, Trotta E, R Simeonov D, Marson A, Bluestone JA, Revisiting IL-2: Biology and therapeutic prospects. Sci Immunol, 2018;3:eaat1482.
Hurton LV, Singh H, Najjar AM, Switzer KC, Mi T, Maiti S, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci USA. 2016;113:E7788–E7797. p.
Google Scholar
Joller N, Anderson AC, Kuchroo VK. LAG-3, TIM-3, and TIGIT: Distinct functions in immune regulation. Immunity. 2024;57:206–22.
Google Scholar
Chiang EY, Mellman I, TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy. J Immunother Cancer 2022;10:e004711.
Zhang P, Liu X, Gu Z, Jiang Z, Zhao S, Song Y, et al. Targeting TIGIT for cancer immunotherapy: recent advances and future directions. Biomark Res. 2024;12:7.
Google Scholar
Chauvin JM, Zarour HM, TIGIT in cancer immunotherapy. J Immunother Cancer 2020;8:e000957.
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T-cell effector function. Cancer Cell. 2014;26:923–37.
Google Scholar
Zhang Q, Bi J, Zheng X, Chen Y, Wang H, Wu W, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol. 2018;19:723–32.
Google Scholar
Guillerey C, Harjunpää H, Carrié N, Kassem S, Teo T, Miles K, et al. TIGIT immune checkpoint blockade restores CD8(+) T-cell immunity against multiple myeloma. Blood. 2018;132:1689–94.
Google Scholar
Kim TW, Bedard PL, LoRusso P, Gordon MS, Bendell J, Oh DY, et al. Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors: A Phase 1a/1b Nonrandomized Controlled Trial. JAMA Oncol. 2023;9:1574–82.
Google Scholar
Rousseau A, Parisi C, Barlesi F. Anti-TIGIT therapies for solid tumors: a systematic review. ESMO Open. 2023;8:101184.
Google Scholar
Niu J, Maurice-Dror C, Lee DH, Kim DW, Nagrial A, Voskoboynik M, et al. First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small cell lung cancer(✩). Ann Oncol. 2022;33:169–80.
Google Scholar
Janjigian YY, Oh DY, Pelster M, Wainberg ZA, Prusty S, Nelson S, et al. Domvanalimab and zimberelimab in advanced gastric, gastroesophageal junction or esophageal cancer: a phase 2 trial. Nat Med. 2025;31:4274–80.
Google Scholar
Wang T, Xu Y, Zhang Z, Wu Y, Chen L, Zheng X, et al. alphaTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T-cell fragility in mouse models. Nat Commun. 2025;16:9223.
Google Scholar
Xu Y, Carrascosa LC, Yeung YA, Chu ML, Yang W, Djuretic I, et al. An Engineered IL15 Cytokine Mutein Fused to an Anti-PD1 Improves Intratumoral T-cell Function and Antitumor Immunity. Cancer Immunol Res. 2021;9:1141–57.
Google Scholar
Matuskova H, Marasek P, Mazhara V, Simonova E, Kosinova L, Danek P, et al., Novel PD-1-targeted, activity-optimized IL-15 mutein SOT201 acting in cis provides antitumor activity superior to PD1-IL2v. J Immunother Cancer, 2025. 13. e010736
Zeng Q, Kong W, Qin Y, Song L, Liu N, Liu Z, et al., Cis-delivering releasable IL-15 superagonist enhances antitumor immunity in cold tumors by invigorating preexisting CD25+CD8+ T cells. bioRxiv, 2025: p. 2025.08.14.670432.
Neri D. Antibody-Cytokine Fusions: Versatile Products for the Modulation of Anticancer Immunity. Cancer Immunol Res. 2019;7:348–54.
Google Scholar
Kiefer JD, Neri D. Immunocytokines and bispecific antibodies: two complementary strategies for the selective activation of immune cells at the tumor site. Immunol Rev. 2016;270:178–92.
Google Scholar
Luke J, Olszanski A, Puzanov I, Fountzilas C, Rosen L. 512 Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in metastatic and advanced solid tumors. J ImmunoTherapy Cancer. 2021;9:A543–A543.
Olson DJ, Eroglu Z, Brockstein B, Poklepovic AS, Bajaj M, Babu S, et al. Phase I dose escalation of KD033, a PDL1-IL15 bispecific molecule, in advanced solid tumors. J Clinical Oncol. 2021;39:2568–2568.
Google Scholar
Rossotti MA, Trempe F, van Faassen H, Hussack G, Arbabi-Ghahroudi M. Isolation and Characterization of Single-Domain Antibodies from Immune Phage Display Libraries. Methods Mol Biol. 2023;2702:107–47.
Google Scholar
Fang Z, Cao D, Qiu J. Development and production of nanobodies specifically against green fluorescence protein. Appl Microbiol Biotechnol. 2020;104:4837–48.
Google Scholar
Liu X, Qiao Y, Chen J, Ge G, Basement membrane promotes tumor development by attenuating T-cell activation. J Mol Cell Biol. 2022;14:mjac006.
Butler A, Hoffman P, Smibert P, Papalexi E, Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat Biotechnol. 2018;36:411–20.
Google Scholar
Yang Q, Safina KR, Nguyen K, Tuong ZK, Borcherding N. scRepertoire 2: Enhanced and efficient toolkit for single-cell immune profiling. PLoS Comput Biol. 2025;21:e1012760.
Google Scholar
Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, et al. TIMER2.0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res. 2020;48:W509–W514.
Google Scholar

