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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Although programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy have improved outcomes in high-risk choriocarcinoma, primary resistance remains a clinically important challenge without reliable predictive biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed data-independent acquisition mass spectrometry (DIA-MS) on pretreatment plasma from a nested discovery subset of 30 patients, followed by enzyme-linked immunosorbent assay (ELISA) assessment of shortlisted candidates in the full cohort of 60 patients. An exploratory two-marker logistic model was developed and internally assessed in the same cohort. Exploratory tissue immunophenotyping and analyses of public tissue-transcriptomic and immunotherapy datasets were used to provide biological context.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>DIA-MS identified a resistance-associated plasma proteomic signature enriched in inflammatory and immunomodulatory mediators among patients with progressive disease. In the full-cohort ELISA assessment, elevated baseline plasma HLA-G and osteopontin (OPN) were associated with primary resistance. The exploratory two-marker model showed an apparent area under the receiver operating characteristic curve of 0.908. In the limited tissue subset, higher HLA-G expression tended to be associated with lower CD8-positive T-cell density, whereas higher OPN expression was associated with increased CD163-positive macrophage density. Public-dataset analyses provided supportive context for associations of HLA-G and SPP1 transcript expression with immune-related programs and unfavorable outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Elevated circulating HLA-G and OPN are associated with resistance to PD-1 inhibitor plus chemotherapy in choriocarcinoma and may serve as candidate minimally invasive biomarkers for pretreatment risk stratification. Independent validation and functional investigation are required before clinical application.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1817862","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T05:38:59Z","timestamp":1785821939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Integrated plasma proteomics identifies HLA-G and osteopontin as circulating biomarkers of resistance to PD-1 inhibitor plus chemotherapy in choriocarcinoma"],"prefix":"10.3389","volume":"17","author":[{"given":"Weidi","family":"Wang","sequence":"first","affiliation":[{"name":"National Clinical Research Center for Women\u2019s Health and Obstetric and Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, 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