{"id":57217,"date":"2026-02-28T01:39:55","date_gmt":"2026-02-28T00:39:55","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/02\/28\/constitutive-stat3-signaling-in-comparison-to-stat5-enhances-car-t-cell-efficacy-and-lowers-systemic-toxicity\/"},"modified":"2026-02-28T01:39:55","modified_gmt":"2026-02-28T00:39:55","slug":"constitutive-stat3-signaling-in-comparison-to-stat5-enhances-car-t-cell-efficacy-and-lowers-systemic-toxicity","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/02\/28\/constitutive-stat3-signaling-in-comparison-to-stat5-enhances-car-t-cell-efficacy-and-lowers-systemic-toxicity\/","title":{"rendered":"Constitutive STAT3 signaling, in comparison to STAT5, enhances CAR T cell efficacy and lowers systemic toxicity"},"content":{"rendered":"<div>\n<p><b>Cancer Immunol Res<\/b>. 2026 Feb 27. doi: 10.1158\/2326-6066.CIR-25-0611. Online ahead of print.<\/p>\n<p><b>ABSTRACT<\/b><\/p>\n<p>Providing cytokine signaling is a key strategy to boost the efficacy of chimeric antigen receptor (CAR) T cell therapy. However, the individual roles of key downstream mediators, STAT3 and STAT5, remain incompletely understood. In this study, we engineered CAR T cells to express constitutively active mutants of STAT3 (Y640F; caSTAT3) and STAT5 (N642H; caSTAT5) to investigate their individual functions. In vitro, caSTAT3 CAR T cells exhibited enhanced effector function and a robust memory phenotype, with broader transcriptional changes involving both effector and memory associated genes compared to caSTAT5 CAR T cells. However, caSTAT3 CAR T cells failed to expand due to activation of apoptosis-related gene programs. In contrast, caSTAT5 CAR T cells demonstrated sustained proliferation over time. Despite the limited in vitro expansion, caSTAT3 CAR T cells exhibited reduced transgene toxicity in vivo and exerted durable antitumor activity in both leukemia and solid tumor models without significant off-tumor toxicity. Titrated expression of caSTAT3 maintained enhanced effector function without inducing apoptosis. On the other hand, caSTAT5 CAR T cells efficiently accumulated in tumors but also infiltrated non-tumor tissues, causing lethal systemic toxicity. Coexpression of caSTAT3 and caSTAT5 markedly enhanced the long-term proliferative capacity of CAR T cells, even in the absence of antigen stimulation or cytokine supplementation. These findings elucidate the distinct impacts of STAT3 and STAT5 activation on CAR T cell behavior and suggest that selective activation of STAT3 at optimal levels may improve CAR T cell efficacy while minimizing off-tumor toxicities.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/41758968\/?utm_source=SimplePie&amp;utm_medium=rss&amp;utm_content=101614637&amp;ff=20260227193946&amp;v=2.19.0.post6+133c1fe\">41758968<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.1158\/2326-6066.CIR-25-0611\">10.1158\/2326-6066.CIR-25-0611<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>Cancer Immunol Res. 2026 Feb 27. doi: 10.1158\/2326-6066.CIR-25-0611. Online ahead of print. ABSTRACT Providing cytokine signaling is a key strategy to boost the efficacy of chimeric antigen receptor (CAR) T cell therapy. However, the individual roles of key downstream mediators, STAT3 and STAT5, remain incompletely understood. In this study, we engineered CAR T cells to &#8230; <a title=\"Constitutive STAT3 signaling, in comparison to STAT5, enhances CAR T cell efficacy and lowers systemic toxicity\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2026\/02\/28\/constitutive-stat3-signaling-in-comparison-to-stat5-enhances-car-t-cell-efficacy-and-lowers-systemic-toxicity\/\" aria-label=\"Read more about Constitutive STAT3 signaling, in comparison to STAT5, enhances CAR T cell efficacy and lowers systemic toxicity\">Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[55,42],"tags":[],"class_list":["post-57217","post","type-post","status-publish","format-standard","hentry","category-cancer-immunology-reserch","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/57217","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=57217"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/57217\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=57217"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=57217"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=57217"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}