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.

Introductory paragraph: Evidence-based dietary recommendations for individuals with inflammatory bowel diseases (IBD) are limited. Red meat consumption is associated with increased IBD incidence and relapse in patients, suggesting that switching to a plant-based diet may limit gut inflammation. However, the mechanisms underlying the differential effects of these diets remain poorly understood. Feeding diets containing plant- or animal-derived proteins to murine colitis models revealed that mice given a beef protein (BP) diet exhibited the most severe colitis, while mice fed pea protein (PP) developed mild inflammation. The colitis-promoting effects of BP were microbially-mediated as determined by bacterial elimination or depletion and microbiota transplant studies. In the absence of colitis, BP-feeding reduced abundance of Lactobacillus johnsonii and Turicibacter sanguinis and expanded Akkermansia muciniphila , which localized to the mucus in association with decreased mucus thickness and quality. BP-fed mice had elevated primary and conjugated fecal bile acids (BAs), and taurocholic acid administration to PP-fed mice worsened colitis. Dietary psyllium protected against BP-mediated inflammation, restored BA-modulating commensals and normalized BA ratios. Collectively, these data suggest that the protein component of red meat may be responsible, in part, for the colitis-promoting effects of this food source and provide insight into dietary factors that may influence IBD severity.

Figure S5 shows muscle weights of CT26 tumor bearing mice fed control or reduced protein diet and receiving 5-FU.

Figure S8 shows western blots and densitometric quantification of pP70S6K expression in tumors.

Figure S1 shows uncropped western blots.