Fasting renders immunotherapy effective against low immunogenic breast cancer while reducing side effects

Immunotherapy is having a major impact in the oncology field by improving the prognosis and survival of cancer patients. However, despite positive results for the treatment of different cancers, a major portion of tumors are resistant to immunotherapy, and the effective combinations of immunotherapy drugs is often accompanied by severe side effects. Here we show that a periodic fasting mimicking diet (FMD), can act on the tumor microenvironment and increase the efficacy of immunotherapy (anti-PD-L1 and anti-OX40), increase the immune response to the poorly immunogenic triple negative breast tumors (TNBC) and reduces the occurrence of immune related adverse events (irAEs). FMD cycles promote the activation of T lymphocytes, remodel tumor microenvironment and induce an immune response even in resistant TNBCs by switching the cancer metabolism from glycolytic to respiratory, by reducing collagen deposition and vessel branching through mTOR repression, and by preventing MDSC infiltration and M2 macrophage polarization in the TME. Furthermore, FMD reverses the lethal effects of immunotherapy by preventing the hyperactivation of the immune response. These results indicate that FMD cycles have the potential to enhance the efficacy of anti-cancer immune responses, expand the range of tumours sensitive to immunotheraoy and reduce its side effects.