Resveratrol as an immune checkpoint inhibitor to enhance the efficacy of breast cancer immunotherapy.

A major goal in cancer treatment is to convert "cold" tumors into "hot" ones by altering the tumor microenvironment (TME). Breast cancer is often a cold tumor and is resistant to immunotherapy. Resveratrol is a polyphenolic compound found in grapes, with antioxidant, anti-inflammatory, and potential cardioprotective and anti-aging properties. Resveratrol promotes the conversion of immunologically cold breast tumors into hot tumors, thereby increasing the efficacy of immunotherapy. This article reviews the potential of resveratrol to convert immunologically "cold" breast tumors into "hot" tumors by modulating the TME and enhancing the efficacy of immunotherapy. A comprehensive literature search was conducted in PubMed, Scopus, Web of Science, and Google Scholar to identify English-language articles investigating the effects of resveratrol on immune checkpoints in breast cancer. The results showed that resveratrol suppresses key cancer-promoting pathways (PI3K/Akt/mTOR, MAPK/ERK, STAT/NF-κB, and Wnt/β-catenin) and modulates the immune system. It boosts anti-tumor immunity by activating immunostimulatory cells (such as M1-TAMs, NKs, and CTLs) while simultaneously inhibiting immunosuppressive cells (such as Tregs and MDSCs). It also acts as a natural immune checkpoint inhibitor by targeting the PD-1/PD-L1 pathway. Resveratrol prevents T-cell exhaustion in "cold" tumors and reduces PD-L1 expression in "hot" tumors, thereby enhancing cytotoxic T cells' ability to attack cancer. However, its effectiveness is limited by poor bioavailability and differences in the biological activity of its metabolites. Future clinical studies are needed to confirm these results and determine optimal therapeutic protocols for resveratrol-mediated breast cancer immunotherapy.