Abstract
Spermidine metabolism influences tumor progression and anti-tumor immunity, thereby affecting treatment sensitivity. However, the precise role and therapeutic potential of spermidine in breast cancer remain unclear. Integrated multi-omics analyses (bulk and single-cell RNA sequencing) revealed a significant positive correlation between intratumoral spermidine abundance and immunophenotypic markers of CD8+ T cell infiltration and activation (GZMB+CD8+ T cells). Immunohistochemical and multiplexed immunohistochemistry validation (IHC/mIHC) demonstrated that breast cancer specimens with elevated spermidine production exhibited increased numbers of activated CD8⁺ T cells. Exogenous supplementation with spermidine promoted CD8⁺ T cell activation directly. Furthermore, supplementing spermidine in vivo promoted anti-tumor immune responses and enhanced sensitivity to anti-PD-1 immunotherapy combined with chemotherapy. Our findings indicate that boosting spermidine metabolism is a promising strategy to reinvigorate CD8⁺ T cell function and improve the efficacy of checkpoint blockade immunotherapy.