SPTSSA in Head and Neck Squamous Cell Carcinoma: Prognostic Significance and Implications for Gene- and Cell-Based Therapy

OBJECTIVE: The Tumor Microenvironment (TME) exerts a pivotal regulatory effect on the initiation, progression, and therapeutic response of Head and Neck Squamous Cell Carcinoma (HNSCC). Serine Palmitoyltransferase Small Subunit A (SPTSSA) is a TME-associated gene with well-characterized roles in multiple malignancies, yet its biological function and clinical significance in HNSCC remain largely elusive. This study aimed to systematically investigate the clinical value of SPTSSA in HNSCC and explore its potential as a novel prognostic biomarker and therapeutic target for this disease. METHODS: The expression of SPTSSA between Head and Neck Squamous Cell Carcinoma (HNSCC) tissues and non-tumoral tissues was compared using gene expression data. Associations with clinicopathologic features and patient outcomes were also analyzed. In vitro assays in HNSCC cell lines were used to test the effects of SPTSSA on malignant phenotypes. Multiplex immunofluorescence histochemistry was applied to assess SPTSSA protein levels in the TME and their relationship with immune markers and clinical factors. Circulating SPTSSA protein levels were measured in the blood of HNSCC patients to evaluate diagnostic value. RESULTS: SPTSSA expression was significantly higher in HNSCC tissues than in non‑tumoral tissues. Overexpression of SPTSSA enhanced HNSCC cell proliferation in vitro, supporting a pro‑tumorigenic function. Elevated SPTSSA protein levels in patient blood suggested potential diagnostic utility. In tumor tissues, SPTSSA protein expression correlated with CD4+ T cells, CD8+ T cells, and CD56+ natural killer cells, indicating a link with immune remodeling in the TME. High SPTSSA expression and advanced TNM stage independently predicted poor clinical outcomes. DISCUSSION: The study's findings establish SPTSSA as a critical oncogenic driver in HNSCC, with its upregulation closely linked to TME immune remodeling and poor patient prognosis. These results expand the oncogenic landscape of HNSCC and align with SPTSSA's pro-tumorigenic roles in other malignancies. Elevated circulating SPTSSA offers a non-invasive diagnostic tool for early detection, while its correlation with immune cell infiltration positions SPTSSA as a promising molecular target for HNSCC immunotherapy. CONCLUSION: SPTSSA is an oncogenic gene that drives HNSCC progression and is closely associated with an unfavorable patient prognosis. Its aberrant expression in both tumor tissues and peripheral blood may facilitate risk stratification and early clinical detection of HNSCC. Furthermore, the correlation between SPTSSA and immune cell infiltration in the TME highlights its potential as a promising molecular target for gene- and cell-based immunotherapeutic strategies in HNSCC.