{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T06:04:40Z","timestamp":1789538680115,"version":"build-2803163510"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Ras signaling plays an essential role in immune cell function; however, its activity must be precisely controlled to prevent excessive activation and associated cellular dysfunction. In this study, we identify the leukocyte-specific Ras GTPase-activating protein (RasGAP) RASAL3 as an important regulator of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell homeostasis and anti-tumor immunity. Following T cell receptor (TCR) stimulation, RASAL3-deficient CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells display sustained Ras activation, resulting in increased activation-induced cell death (AICD). The surviving RASAL3-deficient CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells exhibit impaired effector functions, including reduced cytokine production and decreased tumor-killing activity. Using an\n                    <jats:italic>in vivo<\/jats:italic>\n                    B16-F10 melanoma model, we found that CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell-specific RASAL3-deficient mice (\n                    <jats:italic>\n                      R3\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      Cd8-Cre\n                    <\/jats:italic>\n                    ) develop significantly faster tumor growth compared with control mice. Although Programmed death protein 1 (PD-1) blockade partially restores anti-tumor responses in these mice, the therapeutic effect remains markedly weaker than that observed in control animals. In human melanoma samples, RASAL3 expression is reduced in tumor-infiltrating CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Furthermore, patients with metastatic melanoma show lower RASAL3 expression in primary tumors compared with patients without metastasis, and higher RASAL3 expression in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells within primary lesions is associated with improved overall survival. Together, these findings reveal that RASAL3 is required for the maintenance of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell survival and effector activity. Reduced RASAL3 expression may represent a mechanism by which tumors evade immune surveillance, and RASAL3 expression in CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells may serve as a potential biomarker for predicting clinical outcomes in melanoma.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1893111","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:31:14Z","timestamp":1789536674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ras protein activator-like 3 is a key Ras GTPase-activating protein that protects the survival and anti-tumor activity of CD8+ T cells"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhenzi","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China","place":["Hengyang, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China","place":["Hengyang, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alato","family":"Okuno","sequence":"additional","affiliation":[{"name":"Department of Health and Nutrition, Faculty of Human Design, Shibata Gakuen University","place":["Hirosaki, Aomori, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derick","family":"Okwan-Duodu","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Stanford University","place":["Stanford, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suguru","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, 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