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Italy","award":["AIRC21648"],"award-info":[{"award-number":["AIRC21648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Effective cancer therapies must address the tumor microenvironment (TME), a complex network of tumor cells and stromal components, including endothelial, immune, and mesenchymal cells. Durable outcomes require targeting both tumor cells and the TME while minimizing systemic toxicity. Interleukin-2 (IL-2)-based therapies have shown efficacy in cancers such as metastatic melanoma and renal cell carcinoma but are limited by severe side effects. Innovative IL-2-based immunotherapeutic approaches include immunotoxins, such as antibody\u2013drug conjugates, immunocytokines, and antibody\u2013cytokine fusion proteins that enhance tumor-specific delivery. These strategies activate cytotoxic CD8+ T lymphocytes and natural killer (NK) cells, eliciting a potent Th1-mediated anti-tumor response. Modified IL-2 variants with reduced Treg cell activity further improve specificity and reduce immunosuppression. Additionally, IL-2 conjugates with peptides or anti-angiogenic agents offer improved therapeutic profiles. Combining IL-2-based therapies with immune checkpoint inhibitors (ICIs), anti-angiogenic agents, or radiotherapy has demonstrated synergistic potential. Preclinical and clinical studies highlight reduced toxicity and enhanced anti-tumor efficacy, overcoming TME-driven immune suppression. These approaches mitigate the limitations of high-dose soluble IL-2 therapy, promoting immune activation and minimizing adverse effects. This review critically explores advances in IL-2-based therapies, focusing on immunotoxins, immunocytokines, and IL-2 derivatives. Emphasis is placed on their role in combination strategies, showcasing their potential to target the TME and improve clinical outcomes effectively. Also, the use of IL-2 immunocytokines in \u201cin situ\u201d vaccination to relieve the immunosuppression of the TME is discussed.<\/jats:p>","DOI":"10.3390\/vaccines13010069","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T09:49:17Z","timestamp":1736761757000},"page":"69","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Efficacy of Anti-Cancer Immune Responses Elicited Using Tumor-Targeted IL-2 Cytokine and Its Derivatives in Combined Preclinical Therapies"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8236-2168","authenticated-orcid":false,"given":"Sahar","family":"Balkhi","sequence":"first","affiliation":[{"name":"Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Bilato","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"},{"name":"Unit of Molecular Pathology, Biochemistry and Immunology, IRCCS MultiMedica, 20123 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"De Lerma Barbaro","sequence":"additional","affiliation":[{"name":"Laboratory of Comparative Physiopathology, Department of Biotechnology and Life Sciences, University of Insubria, 20145 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0556-9784","authenticated-orcid":false,"given":"Paola","family":"Orecchia","sequence":"additional","affiliation":[{"name":"Pathology and Experimental Immunology Operative Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1860-430X","authenticated-orcid":false,"given":"Alessandro","family":"Poggi","sequence":"additional","affiliation":[{"name":"SSD Oncologia Molecolare e Angiogenesi, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4757-7101","authenticated-orcid":false,"given":"Lorenzo","family":"Mortara","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and General Pathology, Department of Biotechnology and Life Sciences, University of Insubria, 21100 Varese, Italy"},{"name":"Unit of Molecular Pathology, Biochemistry and Immunology, IRCCS MultiMedica, 20123 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e009722","DOI":"10.1136\/jitc-2024-009722","article-title":"Immune checkpoint blockade: Timing is everything","volume":"12","author":"Sinicrope","year":"2024","journal-title":"J. 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