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.

免疫治疗在肿瘤学领域产生了重大影响，通过改善癌症患者的预后和生存率。尽管在治疗不同癌症方面取得了积极成果，但大部分肿瘤对免疫治疗仍表现出耐药性，而免疫治疗药物的疗效组合常常伴随着严重的副作用。本研究揭示了一种周期性模拟禁食饮食（FMD），能够作用于肿瘤微环境，增强免疫治疗（抗PD-L1和抗OX40）的效果，提高对免疫原性较差的Triple Negative乳腺癌（TNBC）的免疫反应，并降低免疫相关不良事件（irAEs）的发生率。FMD周期通过将癌细胞代谢从糖酵解转变为有氧代谢，通过mTOR抑制减少胶原蛋白沉积和血管分支，以及通过防止MDSC浸润和TME中的M2巨噬细胞极化，促进T淋巴细胞的活化、重塑肿瘤微环境，并在耐药的TNBC中诱导免疫反应。此外，FMD通过防止免疫反应的超活化，逆转了免疫治疗的致命效应。这些结果表明，FMD周期具有增强抗癌症免疫反应的潜力，扩大对免疫治疗敏感的肿瘤范围，并减少其副作用。