{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T01:27:11Z","timestamp":1793582831622,"version":"4.5.0"},"reference-count":53,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,9,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Cancer immunotherapy has reshaped modern oncology by enabling the immune system to recognize and eliminate malignant cells. However, many solid tumors still respond poorly because of weak T\u2010cell activation and an immunosuppressive tumor microenvironment. Bacterial superantigens (SAgs) represent a unique class of immunomodulatory proteins capable of overcoming these limitations through direct activation of large T\u2010cell populations. Unlike conventional antigens, superantigens bypass classical antigen processing by simultaneously binding major histocompatibility complex class II molecules and T\u2010cell receptor V\u03b2 domains, triggering rapid cytokine release and extensive immune activation. Although this potent mechanism has historically been associated with severe systemic toxicity, recent advances in protein engineering and targeted delivery have renewed interest in their therapeutic potential. This review discusses the structural and immunological basis of superantigen activity and highlights emerging strategies designed to improve tumor specificity and safety, including engineered low\u2010toxicity variants, antibody\u2010superantigen fusion proteins, nanoparticle\u2010based delivery systems, and tumor\u2010targeted constructs. We further examine how superantigens reshape the tumor microenvironment and synergize with immune checkpoint blockade, adoptive cell therapies, and other T\u2010cell\u2010redirecting approaches. Together, these advances position engineered superantigens as promising immune\u2010amplifying platforms with the potential to complement existing cancer immunotherapies and improve responses in poorly immunogenic tumors.<\/jats:p>","DOI":"10.1096\/fj.202602532r","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T07:34:57Z","timestamp":1788161697000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Superantigens in Cancer Immunotherapy: Mechanisms, Engineering Strategies, and Therapeutic Potential"],"prefix":"10.1096","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3813-1915","authenticated-orcid":false,"given":"Urooj Yousaf","family":"Virk","sequence":"first","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hafiza Aasia","family":"Malik","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muneera","family":"Anwer","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Wilson","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md. Sifat","family":"Rahi","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming Q.","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Pharmacy and Medical Sciences Griffith University  Southport Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jncc.2025.02.002"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/20503121211034366"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591\u2010018\u20100014\u2010x"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573\u2010018\u20100007\u2010y"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/8052212"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202048747"},{"issue":"7","key":"e_1_2_16_8_1","article-title":"LAG\u20103 Inhibitors: Novel Immune Checkpoint Inhibitors Changing the Landscape of Immunotherapy","volume":"11","author":"Ibrahim R.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.09.011"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.627932"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-021-01075-5"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1125905"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2023.02.004"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12416"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2025.104751"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.3390\/diseases13010024"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00809-z"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2026.1810903"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1127470"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010023\u201000979\u20102"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins11030178"},{"key":"e_1_2_16_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600\u2010065X.2008.00681.x"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0391-5"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1155\/2024\/2313062"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins14110800"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004064\u2010z"},{"key":"e_1_2_16_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202310204"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2023.12.011"},{"key":"e_1_2_16_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.copbio.2019.11.020"},{"key":"e_1_2_16_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.731845"},{"key":"e_1_2_16_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.953678"},{"key":"e_1_2_16_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxins14090595"},{"issue":"4","key":"e_1_2_16_33_1","first-page":"1072","article-title":"Superantigen as a Promising Immunotherapy Treatment Against Cancer: A Review Article","volume":"11","author":"Al Zahrani S. 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