{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T04:18:38Z","timestamp":1787717918037,"version":"build-2784847793"},"reference-count":52,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":13,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin &amp; Trans Imm"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To evaluate the prognostic value of peripheral immune markers and their static and dynamic changes during different treatment stages in patients with hepatitis B virus (HBV)\u2010related unresectable hepatocellula carcinoma (uHCC) receiving transarterial chemoembolisation (TACE) combined with immune checkpoint inhibitors (ICIs) and anti\u2010vascular endothelial growth factor (anti\u2010VEGF) antibodies or tyrosine kinase inhibitors (TKIs).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single\u2010centre retrospective study included patients with HBV\u2010related uHCC treated with TACE combined with ICls and anti\u2010VEGF antibodies or TKIs between July 2019 and July 2024. Peripheral blood immune indicators were collected at baseline (Cycle 0), the second treatment cycle (Cycle 2) and the fourth treatment cycle (Cycle 4). The primary outcome was overall survival (OS), while secondary outcomes included progression\u2010free survival (PFS), objective response rate (ORR) and disease control rate (DCR), with tumour response assessed at the first treatment evaluation (at the end of the fourth treatment cycle) based on mRECIST criteria. Longitudinal changes between adjacent time points were calculated (\u0394: Cycle 2 \u2010 Cycle 0; \u03942: Cycle 4 \u2010 Cycle 2). Both static values and dynamic changes in immune markers were subjected to LASSO\u2010Cox and stepwise multivariate Cox regression analyses to identify independent predictors of OS. Based on the significant variables, a prognostic nomogram and an immune\u2010based risk score model were developed. To further assess prognostic heterogeneity, patients were stratified by K\u2010means clustering according to the temporal patterns of the most predictive immune marker, and survival outcomes were compared across the resulting subgroups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 67 HBV\u2010related uHCC patients treated with TACE plus ICIs and anti\u2010VEGF antibodies\/TKIs were included. The cohort had a median follow\u2010up of 18.2\u2009months, with a median overall survival (mOS) of 30.4\u2009months and a median progression\u2010free survival (mPFS) of 11.0\u2009months. At the first evaluation, the objective response rate (ORR) was 53.7%, and the disease control rate (DCR) was 86.6%. LASSO\u2010Cox regression identified several static and dynamic immune markers associated with OS. Ultimately, CD4\u207a\/CD8\u207a ratio at Cycle 4 (HR\u2009=\u20090.58,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.035), \u03942 NLR (HR\u2009=\u20091.66,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.014), and \u03942 CD3\u207aCD4\u207a (HR\u2009=\u20090.04,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.007) were confirmed by stepwise multivariate Cox regression. A prognostic nomogram incorporating these variables demonstrated favourable predictive performance (C\u2010index\u2009=\u20090.72; AUCs\u2009=\u20090.750, 0.722 and 0.854 for 1\u2010, 2\u2010 and 3\u2010year OS, respectively). The derived immune\u2010based risk score effectively stratified patients into high\u2010 and low\u2010risk groups with significantly different OS (11.5 vs. 34.0\u2009months,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) and PFS (7.5 vs. 13.8\u2009months,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.006). The risk score showed a positive correlation with \u03942 NLR (\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u20090.50) and negative correlations with CD4\u207a\/CD8\u207a ratio (\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u2009\u22120.64) and \u03942 CD3\u207aCD4\u207a (\n                      <jats:italic>r<\/jats:italic>\n                      \u2009=\u2009\u22120.45). Based on CD3\u207aCD4\u207a trajectory clustering, three distinct immune dynamic subtypes were identified, among which the continuous decline group exhibited the poorest prognosis (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.042).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study demonstrates the prognostic relevance of peripheral immune markers in patients with HBV\u2010related uHCC receiving combination therapy. Immune dynamics observed during later treatment stages, rather than baseline measurements, were more strongly associated with overall survival. A risk model based on the CD4\u207a\/CD8\u207a ratio at Cycle 4, \u03942 NLR and \u03942 CD3\u207aCD4\u207a enabled effective prognostic stratification and may provide a useful framework for risk assessment in this patient population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cti2.70115","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T01:25:48Z","timestamp":1786757148000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral immune dynamics during treatment predict prognosis in\n                    <scp>HCC<\/scp>\n                    receiving\n                    <scp>TACE<\/scp>\n                    plus\n                    <scp>ICIs<\/scp>\n                    and anti\u2010\n                    <scp>VEGF<\/scp>\n                    \/\n                    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