GINS2 Promotes Oral Squamous Cell Carcinoma Progression and Immune Evasion by Recruiting PD-L1+ Neutrophils and Modulating the PTP4A1/PKM2 Axis

Bo Wei¹Jiajia Yin¹Chuyan Shi¹Hui Sun¹Bing Liu²Peng Chen^1*

• ¹1st Medical Center of Chinese PLA General Hospital, Beijing, China
• ²Air Force Medical Center of Chinese PLA Air Force Medical University, Beijing, China

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 in vivo 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 in vitro and immune-reconstituted in vivo 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 in vitro, and inhibited tumor growth in vivo. 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) in vivo, 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.