(+)‐Matairesinol, Derived From Olive Oil, Enhanced T‐Cell Anti‐Tumor Immune via <scp>JAK3</scp> ‐ <scp>STAT1</scp> Signal and Synergized With Anti‐ <scp>PD</scp> ‐1 Efficacy

Extra virgin olive oil (EVOO) is one of the signature foods for cooking and dressing in the Mediterranean diet, and clinical evidence revealed its remarkably lower risk of breast cancer. However, the current anti-tumor constituent studies rarely supported this clinical effect. Thus, it might contain a novel mechanism, and should be clarified. The nontraditional cytotoxicity T-cell immunomodulatory anti-tumor model combination with bioactivity-guided isolation was used to explore its bioactive compound and mechanism. The LDH killing and ELISA analysis were used to examine killing efficacy and cytokines. The mouse breast cancer lung metastasis model was used to evaluate anti-tumor efficacy in vivo through EVOO monotherapy combined with anti-PD-1 treatment. The proteome and phosphoproteome analyses were used to mechanistic study combined with blocking rescue analysis. It revealed that EVOO lignans had promising T-cell immune anti-tumor activity in vitro and in vivo, particularly in a mice triple-negative breast cancer (TNBC) model; the lung metastasis was remarkably reduced about 59%, and improved 38% overall survival. Moreover, it synergized with anti-PD-1, boosting 53% efficacy. Furthermore, bioactivity-guided isolation revealed the compound (+)-matairesinol was identified as the potential T-cell immunomodulator, proteomic and phosphoproteomic analyses combined with blocking rescue experiments revealed that it promoted T-cell immune major through enhancing JAK3-STAT1 signal to upregulate granzyme B (GZMB), interferon gamma (IFN-γ) to kill multiple tumor cells. These findings could support EVOO to serve as dietary-based cancer prevention or combination immunotherapy and first revealed the T-cell immune anti-tumor mechanism and its bioactive compound involved in EVOO cancer prevention.