GINS2 promotes oral squamous cell carcinoma progression and immune evasion by recruiting PD-L1 neutrophils and modulating the PTP4A1/PKM2 axis.

[INTRODUCTION] 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.

[METHODS] 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 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 T cells were quantified by flow cytometry in co-culture. Neutrophil features (PD-L1 expression) and interventions (neutrophil depletion, anti-PD-L1) were evaluated and immune-reconstituted settings.

[RESULTS] 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 , and inhibited tumor growth . 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 T cells. GINS2 expression also correlated with neutrophil infiltration; GINS2 overexpression increased tumor-associated neutrophils (TANs) , 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.

[DISCUSSION] GINS2 acts as a key oncogenic driver in OSCC, promoting tumor progression and facilitating immune evasion. Its effects appear to involve a proximal GINS2-PTP4A1-PKM2 module and the recruitment/polarization of PD-L1 neutrophils linked to T-cell dysfunction. Targeting the GINS2 axis-potentially in combination with PD-L1 blockade-warrants further investigation in OSCC, with downstream signaling mechanisms to be clarified in future work.