Ketogenic diet inhibits tumor growth by enhancing immune response, attenuating immunosuppression, inhibiting angiogenesis and EMT in CT26 colon tumor allografts mouse model

[Display omitted] •KD enhanced the activity of Th1 cells and promoted cellular immune function in a CT26 colon tumor allografts mouse model.•KD increased CD8+ T cells and decreased CD4+ FoxP3+ T cells in tumor tissues and spleen of mouse model.•KD inhibited the expression of PD-L1 and CTLA4.•KD promoted tumor apoptosis in CT26 mouse model.•KD suppressed intramural angiogenesis and epithelial-to-mesenchymal transition (EMT). Ketogenic diet (KD) has increasingly captured the attention of researchers due to its anti-tumor activity. Here, we found that KD treatment significantly enhanced tumor-reactive immune responses, including increased intratumoral CD8+ and CD4+ T cells and decreased FOXP3+/CD4+ Treg cells. Moreover, KD administration increased the Th1-related cytokines IL-2, IFN-γ, IL-1α and IL-12, while decreased Th2-related cytokines IL-4, IL-13 and COX-2, as well as reduced the expression of PD-L1 and CTLA4. Further evaluation revealed that tumor vascularization decreased dramatically after KD treatment. Furthermore, KD reversed the epithelial-mesenchymal transition (EMT) in microenvironmental by up-regulation of E-cadherin, down-regulation of N-cadherin and vimentin. Additionally, KD decrease the expression of phosphorylated STAT1/STAT1, while promoting the expression of P53, Bax/Bcl-2 and caspase-3 in tumor tissues. Thus, our findings indicate that KD treatment can enhance the anti-tumor immunity and mitigate the tumor immunosuppression in the tumor microenvironment, as well as decrease the tumor vascularization.