{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:41:24Z","timestamp":1793727684694,"version":"4.6.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"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:sec><jats:title>Background<\/jats:title><jats:p>Human leukocyte antigen (HLA)-G has multiple isoforms with unique molecular structures and receptor-binding specificities. Different HLA-G isoform(s) may have distinct clinical relevance. Because of the lack of isoform-specific monoclonal antibodies (mAbs), the clinical significance of HLA-G isoforms (HLA-G1 to HLA-G7), except HLA-G1 and HLA-G5, remains largely unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this study, mAbs against HLA-G2\/6 and HLA-G1\/4\/5 isoforms were generated and characterized. Expression of HLA-G2\/6 and HLA-G1\/4\/5 isoforms was analyzed by immunohistochemistry, and clinical significance was evaluated retrospectively in 345 patients with colorectal cancer (CRC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The expression rate of HLA-G2\/6 (90\/345, 26.1%) was significantly lower than that of HLA-G1\/4\/5 (275\/345, 79.7%; <jats:italic>p<\/jats:italic> &amp;lt; 0.001). Patients with HLA-G2\/6 expression had significantly poorer overall survival (OS) (median OS: 6.3 years [95% CI: 4.1\u20138.5] <jats:italic>vs<\/jats:italic>. 10.0 years [95% CI: 7.6\u201312.4]; <jats:italic>p<\/jats:italic> = 0.008). Multivariate Cox proportional-hazard model results indicated that HLA-G2\/6 was an independent prognostic factor for CRC (hazard ratio [HR] = 1.530, 95% CI: 1.125\u20132.081; <jats:italic>p<\/jats:italic> = 0.007). Moreover, HLA-G2\/6 expression showed stratified prognostic significance among several CRC patient subgroups, specifically in female patients (p = 0.003), younger patients (&amp;lt;66 years p &amp;lt; 0.001), patients with colon cancer (<jats:italic>p<\/jats:italic> = 0.045), those at stage pT3 (<jats:italic>p<\/jats:italic> = 0.008), pN1 (<jats:italic>p<\/jats:italic> = 0.020), <jats:italic>p<\/jats:italic>M0 (<jats:italic>p<\/jats:italic> = 0.009), and AJCC stage III (<jats:italic>p<\/jats:italic> = 0.005). However, no statistical significance was found between HLA-G1\/4\/5 isoform expression and patient prognosis in CRC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This is the first study to generate mAbs for the HLA-G2\/6 and HLA-G1\/4\/5 isoforms. Our findings reveal that HLA-G2\/6\u2014but not HLA-G1\/4\/5\u2014expression is an independent prognostic indicator for patients with CRC. In the context of precision medicine, our study also suggests that HLA-G isoform typing may be necessary for HLA-G-targeted cancer immunotherapy.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1672144","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:08:59Z","timestamp":1761041339000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Human leukocyte antigen-G isoform HLA-G2\/6, but not HLA-G1\/4\/5, is an independent indicator of poor survival in patients with colorectal 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