{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:19:25Z","timestamp":1790399965042,"version":"4.1.0"},"reference-count":33,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, the adoption of high-dose rhIL-2 has been restricted by its severe treatment-related adverse event (TRAE) profile, which necessitates highly experienced clinical providers familiar with rhIL-2 administration and readily accessible critical care medicine support. Given the comparatively wide-ranging successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies, there have been concerted efforts to significantly improve the efficacy and toxicities of IL-2-based immunotherapeutic approaches. In this review, we highlight novel drug development strategies, including biochemical modifications and engineered IL-2 variants, to expand the narrow therapeutic window of IL-2 by leveraging downstream activation of the IL-2 receptor to selectively expand anti-tumor CD8-positive T cells and natural killer cells. These modified IL-2 cytokines improve single-agent activity in solid tumor malignancies beyond the established United States Food and Drug Administration (FDA) indications of metastatic melanoma and renal cell carcinoma, and may also be safer in rational combinations with established treatment modalities, including anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches.<\/jats:p>","DOI":"10.3390\/cells12091316","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T02:56:51Z","timestamp":1683255411000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Rethinking Oncologic Treatment Strategies with Interleukin-2"],"prefix":"10.3390","volume":"12","author":[{"given":"Brian","family":"Ko","sequence":"first","affiliation":[{"name":"Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5790-4954","authenticated-orcid":false,"given":"Naoko","family":"Takebe","sequence":"additional","affiliation":[{"name":"Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omozusi","family":"Andrews","sequence":"additional","affiliation":[{"name":"Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4068-7375","authenticated-orcid":false,"given":"Monish Ram","family":"Makena","sequence":"additional","affiliation":[{"name":"Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-853X","authenticated-orcid":false,"given":"Alice P.","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cancer Treatment & Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Gatla, H.R., Muniraj, N., Thevkar, P., Yavvari, S., Sukhavasi, S., and Makena, M.R. (2019). Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051110"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"(2019). Cytokines in the balance. Nat. Immunol., 20, 1557.","DOI":"10.1038\/s41590-019-0557-0"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S34","DOI":"10.1002\/eji.200737772","article-title":"Historical insights into cytokines","volume":"37","author":"Dinarello","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1984","DOI":"10.1002\/pro.3519","article-title":"The molecular details of cytokine signaling via the JAK\/STAT pathway","volume":"27","author":"Morris","year":"2018","journal-title":"Protein Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1038\/s41568-021-00363-z","article-title":"Interleukins in cancer: From biology to therapy","volume":"21","author":"Briukhovetska","year":"2021","journal-title":"Nat. Rev. Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1038\/s41591-020-1051-9","article-title":"An inflammatory cytokine signature predicts COVID-19 severity and survival","volume":"26","author":"Huang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4309485","DOI":"10.1155\/2017\/4309485","article-title":"Cytokines as biomarkers and their respective clinical cutoff levels","volume":"2017","author":"Monastero","year":"2017","journal-title":"Int. J. Inflamm."},{"key":"ref_8","unstructured":"Vaillant, A.A.J., and Qurie, A. (2021). StatPearls, StatPearls Publishing."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1126\/science.181845","article-title":"Selective in vitro growth of T lymphocytes from normal human bone marrows","volume":"193","author":"Morgan","year":"1976","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.3389\/fimmu.2018.02987","article-title":"Regulation of effector and memory CD8 T cell differentiation by IL-2\u2014A balancing act","volume":"9","author":"Kalia","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.immuni.2013.01.004","article-title":"Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy","volume":"38","author":"Liao","year":"2013","journal-title":"Immunity"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1146\/annurev-immunol-042617-053352","article-title":"Signaling and function of interleukin-2 in T lymphocytes","volume":"36","author":"Ross","year":"2018","journal-title":"Annu. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12943-017-0721-9","article-title":"Tumor-related interleukins: Old validated targets for new anti-cancer drug development","volume":"16","author":"Setrerrahmane","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1056\/NEJM198512053132327","article-title":"Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer","volume":"313","author":"Rosenberg","year":"1985","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s10020-021-00321-3","article-title":"Immersion in the search for effective cancer immunotherapies","volume":"27","author":"Rosenberg","year":"2021","journal-title":"Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5451","DOI":"10.4049\/jimmunol.1490019","article-title":"IL-2: The first effective immunotherapy for human cancer","volume":"192","author":"Rosenberg","year":"2014","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1097\/00000658-199809000-00004","article-title":"Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: Identification of the antigens mediating response","volume":"228","author":"Rosenberg","year":"1998","journal-title":"Ann. Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114112","DOI":"10.1016\/j.addr.2022.114112","article-title":"Engineering interferons and interleukins for cancer immunotherapy","volume":"182","author":"Holder","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11906","DOI":"10.1073\/pnas.1002569107","article-title":"Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells","volume":"107","author":"Krieg","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1163462","DOI":"10.1080\/2162402X.2016.1163462","article-title":"Role of IL-2 in cancer immunotherapy","volume":"5","author":"Jiang","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.immuni.2010.08.004","article-title":"Interleukin-2 receptor signaling: At the interface between tolerance and immunity","volume":"33","author":"Malek","year":"2010","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1586\/1744666X.2014.875856","article-title":"Challenges and developing solutions for increasing the benefits of IL-2 treatment in tumor therapy","volume":"10","author":"Skrombolas","year":"2014","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_23","first-page":"w14697","article-title":"Development of a novel class of interleukin-2 immunotherapies for metastatic cancer","volume":"149","author":"Boyman","year":"2019","journal-title":"Swiss Med. Wkly."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e000673","DOI":"10.1136\/jitc-2020-000673","article-title":"ALKS 4230: A novel engineered IL-2 fusion protein with an improved cellular selectivity profile for cancer immunotherapy","volume":"8","author":"Lopes","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1124\/jpet.121.000612","article-title":"Pharmacokinetics and pharmacodynamic effects of nemvaleukin alfa, a selective agonist of the intermediate-affinity IL-2 receptor, in cynomolgus monkeys","volume":"379","author":"Lopes","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2500","DOI":"10.1200\/JCO.2022.40.16_suppl.2500","article-title":"Nemvaleukin alfa monotherapy and in combination with pembrolizumab in patients (pts) with advanced solid tumors: ARTISTRY-1","volume":"40","author":"Ulka","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1200\/JCO.2021.39.15_suppl.2552","article-title":"Selection of the recommended phase 2 dose (RP2D) for subcutaneous nemvaleukin alfa: ARTISTRY-2","volume":"39","author":"Hamid","year":"2021","journal-title":"J. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7850","DOI":"10.1016\/j.annonc.2022.07.911","article-title":"First disclosure of efficacy and safety of bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) vs NIVO monotherapy in advanced melanoma (MEL)","volume":"33","author":"Diab","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S808","DOI":"10.1016\/j.annonc.2022.08.073","article-title":"Bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) compared to the investigator\u2019s choice of sunitinib or cabozantinib in previously untreated advanced renal cell carcinoma (RCC): Results from a phase III randomized study (PIVOT-09)","volume":"33","author":"Tannir","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1158\/1538-7445.AM2021-LB041","article-title":"THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced\/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1\/2 Study","volume":"81","author":"Janku","year":"2021","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nature24659","article-title":"A semi-synthetic organism that stores and retrieves increased genetic information","volume":"551","author":"Zhang","year":"2017","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e004991","DOI":"10.1136\/jitc-2022-004991","article-title":"TransCon IL-2 beta\/gamma: A novel long-acting prodrug with sustained release of an IL-2Rbeta\/gamma-selective IL-2 variant with improved pharmacokinetics and potent activation of cytotoxic immune cells for the treatment of cancer","volume":"10","author":"Rosen","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7855808","DOI":"10.1155\/2021\/7855808","article-title":"Interleukin 2-Based Fusion Proteins for the Treatment of Cancer","volume":"2021","author":"MacDonald","year":"2021","journal-title":"J. Immunol. Res."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:29:32Z","timestamp":1760124572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/9\/1316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,5]]},"references-count":33,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12091316"],"URL":"https:\/\/doi.org\/10.3390\/cells12091316","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,5]]}}}