Facilitation of natural killer T-cell cytotoxic activity in uterine sarcoma via the CKS2-PI3K-AKT-MICA axis.

Abstract

Background: Uterine sarcoma constitutes approximately 3-7% of all uterine cancers, with adenosarcoma and leiomyosarcoma being the major subtypes. This neoplasm is characterized by poor clinical outcomes, with frequent recurrence and metastasis, underscoring the urgent need for early detection strategies. Cyclin-dependent kinase regulatory subunit 2 (CKS2) is markedly overexpressed in uterine sarcoma. Preliminary data suggest that CKS2 overexpression correlates with advanced tumor staging, yet its mechanistic link to immune evasion via natural killer T (NKT)-cell regulation remains unexplored. This study aimed to explore how CKS2 regulates the immune response in uterine sarcoma.

Methods: Through the integration of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, a systematic analysis was conducted on the correlation between CKS2 expression levels, tumor prognostic staging, and immune cell infiltration. Stable CKS2-knockdown cell lines were constructed, and the expression changes of CKS2 were detected via quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot techniques. Through colony formation assays, TUNEL staining, invasion and migration assays, and Western blot analysis, the mechanism related to the regulatory effect of CKS2 on the malignant progression of uterine sarcoma cells was clarified in depth. Additionally, the specific mechanism by which CKS2 regulates NKT cell activity was verified at the tissue level via multiplex immunofluorescence.

Results: In uterine sarcoma, CKS2 expression was found to be significantly upregulated and closely associated with poor prognosis, advanced tumor stage, and a distinct negative correlation with NKT cell activity. In vitro experiments indicated that knockdown of CKS2 significantly inhibited the proliferation, migration, and invasion of sarcoma cells and promoted apoptosis. Mechanistically, CKS2 activated the PI3K/AKT signaling, reduced major histocompatibility complex (MHC) class I chain-related protein A (MICA) expression, and inhibited NKT cell activity, resulting in immune escape, which was effectively mitigated by PI3K inhibitors.

Conclusions: The findings suggest that CKS2 can serve as a valuable biomarker and an effective target for the prevention and screening of uterine sarcoma and can modify the antitumor immune response in uterine sarcoma.