{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T12:18:43Z","timestamp":1790684323992,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"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>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The GINS complex subunit 2 (GINS2) is crucial for DNA replication, but its specific roles in oral squamous cell carcinoma (OSCC) pathogenesis and tumor microenvironment (TME) modulation are poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      GINS2 expression was analyzed using TCGA data and validated in OSCC patient tissues and cell lines via qPCR, Western blot (WB), and immunohistochemistry (IHC). Functional assays (CCK-8, colony formation, wound healing, Transwell invasion) and\n                      <jats:italic>in vivo<\/jats:italic>\n                      xenograft models assessed the impact of GINS2 knockdown (sh-GINS2) or overexpression (OE-GINS2) on OSCC cell behavior and tumorigenesis. Mechanistic links involving PTP4A1 and PKM2 were explored using Co-immunoprecipitation (Co-IP) and immunofluorescence (IF). Immune correlations were assessed in TCGA\/TIMER2.0 (PDCD1, LAG3, CTLA4, HAVCR2), and PD-1\/TIM-3 on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were quantified by flow cytometry in co-culture. Neutrophil features (PD-L1 expression) and interventions (neutrophil depletion, anti-PD-L1) were evaluated\n                      <jats:italic>in vitro<\/jats:italic>\n                      and immune-reconstituted\n                      <jats:italic>in vivo<\/jats:italic>\n                      settings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GINS2 was significantly upregulated in OSCC tissues and cell lines, correlating with advanced clinical stage and higher pathological grade. GINS2 knockdown suppressed proliferation, colony formation, migration, and invasion\n                      <jats:italic>in vitro<\/jats:italic>\n                      , and inhibited tumor growth\n                      <jats:italic>in vivo<\/jats:italic>\n                      . At the protein level, GINS2 physically associated with PTP4A1 and monotonically modulated its steady-state abundance; PTP4A1 interacted and co-localized with PKM2. In TCGA, GINS2 expression positively correlated with T-cell exhaustion markers, and altering GINS2 in OSCC cells changed PD-1 and TIM-3 on co-cultured CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. GINS2 expression also correlated with neutrophil infiltration; GINS2 overexpression increased tumor-associated neutrophils (TANs)\n                      <jats:italic>in vivo<\/jats:italic>\n                      , and Ly6G neutrophil depletion attenuated GINS2-driven tumor enhancement. OSCC-associated neutrophils exhibited elevated PD-L1 expression, correlating positively with GINS2 levels. GINS2 knockdown sensitized OSCC models to anti-PD-L1 therapy, reducing tumor growth and Ki67 expression, particularly when combined with T cells and neutrophils.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      GINS2 acts as a key oncogenic driver in OSCC, promoting tumor progression and facilitating immune evasion. Its effects appear to involve a proximal GINS2\u2013PTP4A1\u2013PKM2 module and the recruitment\/polarization of PD-L1\n                      <jats:sup>+<\/jats:sup>\n                      neutrophils linked to T-cell dysfunction. Targeting the GINS2 axis\u2014potentially in combination with PD-L1 blockade\u2014warrants further investigation in OSCC, with downstream signaling mechanisms to be clarified in future work.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1637296","type":"journal-article","created":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T05:22:09Z","timestamp":1762320129000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["GINS2 promotes oral squamous cell carcinoma progression and immune evasion by recruiting PD-L1+ neutrophils and modulating the PTP4A1\/PKM2 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