FSTL3-Driven Cuproptosis Resistance and EPCs Promote OSCC Metastasis

Abstract

Lymph node metastasis, critically dependent on evasion of cancer cell death, drives poor prognosis in oral squamous cell carcinoma (OSCC). Through CRISPR-Cas9 screening in OSCC cell lines with divergent metastatic potential, we identified follistatin-like 3 (FSTL3) as a master regulator of lymph node metastasis. Fstl3 knockdown drastically suppressed metastasis. Mechanistically, FSTL3 loss induced cuproptosis susceptibility by suppressing SLC25A10, triggering mitochondrial succinate accumulation. Succinate promoted succinylation and upregulation of dihydrolipoamide S-acetyltransferase (DLAT), essential for cuproptosis execution, thereby crippling metastatic spread. Crucially, FSTL3 simultaneously orchestrates an immunosuppressive tumor microenvironment. FSTL3 recruits erythroid progenitor cells (EPCs) into tumor sites by upregulating CCR5 on EPCs. Concurrently, FSTL3-exposed EPCs exhibited elevated CD73 and PD-L1, establishing an immunosuppressive niche that promotes metastasis. Consequently, FSTL3 depletion in immunotherapy-resistant tumors unleashed potent antitumor immunity and synergized with immunotherapy. Our findings establish FSTL3 as a pivotal node coordinating dual metastasis mechanisms: cuproptosis resistance and immune evasion. Targeting FSTL3 disrupts both adaptive programs, effectively inhibiting lymph node metastasis. This work nominates FSTL3 as a therapeutic target; combining FSTL3 inhibition with immunotherapy represents a promising dual-targeting strategy to improve OSCC outcomes by simultaneously disabling cancer cell survival and immune escape.

Keywords

oral carcinogenesis follistatin-like 3 erythroid progenitor cells cell death immunotherapy lymphatic metastasis

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