Short-Term Fasting Synergizes with Solid Cancer Therapy by Boosting Antitumor Immunity

Abstract

Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy.

Keywords: cancer immunity; cancer therapy; chemotherapy; fasting mimicking diet; immunomodulation; immunotherapy; short-term fasting.

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Figure 2

Immunomodulatory mechanisms of short-term fasting [STF] during anticancer therapy. STF reduces immunosuppression and enhances antitumor immunity via the following mechanisms established from preclinical studies: CD73 downregulation in cancer cells causes decreased adenosine release, which in turn diminishes immunosuppressive M2-type macrophage polarization. Decreased heme oxygenase-1 (HO-1) production by cancer cells (and M2 macrophages) releases inhibition of regulatory T (Tregs) cells on CD8+ cytotoxic T cells directly as well as direct inhibition from HO-1. Lowered glycolysis inhibits macrophage and granulocyte colony-stimulating factor (M-CSF, G-CSF) secretion by cancer cells. Consequently less myeloid derived suppressor cells are mobilized from the bone marrow. Hematopoietic stem cell regeneration of common lymphoid progenitors (CLP), naïve T cells and accumulation of memory T cells is observed centrally. Peripheral increase of CD8+ and CD4+ T cells is observed after refeeding and might replenish exhausted T cells as well as increase tumor antigen recognition chance. Autophagy induction stimulates tumoricidal M1 macrophage differentiation, which can support antitumor immunity. Figure 2 is adapted from “Cancer Immunoediting”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.