Reducing Dietary Protein Enhances the Antitumor Effects of Chemotherapy through Immune-Mediated Mechanisms

Diet is believed to be an important mediator of oncogenesis and response to anticancer therapies although no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress and enhancing antitumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of chemotherapy, the most widely used anticancer treatment. In this study, we present evidence that reducing protein intake in mice by 50% stops the growth of established tumors, in parallel with inducing a stress response and DNA damage. Further, a reduced protein (RP) diet enhances tumor regression upon treatment with 5-fluorouracil (5-FU). This effect is accompanied by elevated apoptosis and suppressed mitosis of tumor cells. Proteomic analysis of tumors revealed marked differences between 5-FU-treated mice fed a control diet and those fed an RP diet, including decreased abundance of proteins that mediate DNA repair and replication in mice consuming RP. In vitro studies mimicking amino acid changes found in tumors from RP-fed mice showed that cGAS/STING1 signaling, including transcription of Ifnb1, was maximally increased in 5-FU-treated cells cultured in modified amino acid medium. These findings correlated with enhanced immune cell influx into tumors from mice treated with 5-FU while consuming an RP diet, an effect that was causally linked to improved response to chemotherapy. Collectively, these findings suggest that reducing dietary protein in patients with cancer may enhance the efficacy of chemotherapy by promoting antitumor immunity.