{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T13:08:33Z","timestamp":1788872913138,"version":"build-2803163510"},"reference-count":84,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"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>Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) exists not only as a membrane-bound immune checkpoint but also as a naturally secreted soluble isoform (sCTLA-4), generated primarily through exon 3 skipping. This review focuses specifically on splice-derived sCTLA-4 and examines its biological and clinical significance. sCTLA-4 is shaped by immune state, cellular source, and tissue microenvironment. Mechanistically, sCTLA-4 can restrain B7\/CD28-dependent immune activation, while recent preclinical evidence suggests a preferential effect on type 1 immune responses. In autoimmune and inflammatory diseases, longitudinal changes in sCTLA-4 often parallel changes in immune activity, although its performance as a disease-specific biomarker remains limited. In cancer, associations with tumor burden, prognosis, and treatment response are more variable and appear to depend strongly on the surrounding immune context. Thus, circulating sCTLA-4 may be better viewed as a state-dependent immunoregulatory signal than as a universal standalone biomarker. Current evidence does not clearly establish whether its elevation is causal, compensatory, or epiphenomenal. Key translational priorities include detection methods that distinguish sCTLA-4 isoforms and cellular sources, standardized longitudinal sampling, biomarker panels that integrate sCTLA-4 with defined immune phenotypes, and therapeutic strategies tailored to specific immune contexts while preserving peripheral tolerance.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1939265","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:29:20Z","timestamp":1788870560000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Soluble CTLA-4 as a context-dependent immune checkpoint: biology, biomarker potential, and therapeutic implications"],"prefix":"10.3389","volume":"17","author":[{"given":"Xue","family":"Cai","sequence":"first","affiliation":[{"name":"Center of Integrative Medicine, Beijing Ditan Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Dongfang Hospital, Beijing 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