FSCN1 Modulates Tumor Growth and Innate Immune Pathways through Synergistic Interaction with PIK3CA Mutations

Background Tumor-specific genetic alterations critically drive cancer progression and therapeutic resistance through both cell- and non-cell-autonomous mechanisms. While the actin-binding protein FSCN1 has been linked to tumor progression, its role in shaping immune evasion and tumor growth in PIK3CA-mutant cancers remains poorly understood. This study investigated the mechanism by which FSCN1 modulates the tumor immune microenvironment and malignant progression in PIK3CA-mutant malignancies, with implications for therapeutic targeting. Methods To dissect FSCN1 function, we used PIK3CA-mutant CaSki cervical cancer cells and PIK3CA wild-type HeLa cells. Transcriptomic profiling and gene ontology (GO) analyses were performed following FSCN1 knockdown to identify pathway alterations. Clinical relevance was assessed using TCGA datasets to evaluate the FSCN1-associated prognostic trends and immune cell infiltration. In vivo validation utilized xenograft models of FSCN1-depleted CaSki and HeLa tumors to quantify growth suppression and immune microenvironment remodeling. Results FSCN1 knockdown in PIK3CA-mutant CaSki cells (but not HeLa cells) robustly activated innate immune and interferon signaling while suppressing mitotic regulators. GO enrichment revealed that FSCN1 suppression upregulated T-cell activation pathways and enhanced immune-mediated tumor suppression, specifically in PIK3CA-mutant cells. High FSCN1 expression in PIK3CA-mutant TCGA tumors was correlated with poor prognosis and reduced dendritic cell (DC) infiltration, suggesting immune evasion. FSCN1 depletion markedly inhibited CaSki tumor growth and increased intratumoral DC recruitment in mice, whereas HeLa tumors remained unaffected. Conclusions FSCN1 promotes immune evasion and tumor progression in PIK3CA-mutant cancers via dual mechanisms: suppression of innate immune activation and sustained mitotic proliferation. Clinically, elevated FSCN1 levels predict diminished DC infiltration and unfavorable outcomes. Targeting FSCN1 may disrupt these pathways, offering a strategy to reprogram the immunosuppressive tumor microenvironment and improve therapeutic responses in PIK3CA-mutant malignancies.