Targeting cancer metabolic pathways for improving chemotherapy and immunotherapy

Abstract

Recent discoveries in cancer metabolism have revealed promising metabolic targets to modulate cancer progression, drug response, and anti-cancer immunity. Combination therapy, consisting of metabolic inhibitors and chemotherapeutic or immunotherapeutic agents, offers new opportunities for improved cancer therapy. However, it also presents challenges due to the complexity of cancer metabolic pathways and the metabolic interactions between tumor cells and immune cells. Many studies have been published demonstrating potential synergy between novel inhibitors of metabolism and chemo/immunotherapy, yet our understanding of the underlying mechanisms remains limited. Here, we review the current strategies of altering the metabolic pathways of cancer to improve the anti-cancer effects of chemo/immunotherapy. We also note the need to differentiate the effect of metabolic inhibition on cancer cells and immune cells and highlight nanotechnology as an emerging solution. Improving our understanding of the complexity of the metabolic pathways in different cell populations and the anti-cancer effects of chemo/immunotherapy will aid in the discovery of novel strategies that effectively restrict cancer growth and augment the anti-cancer effects of chemo/immunotherapy.

Keywords: Cancer metabolism; Cancer nanotechnology; Chemotherapy; Immunotherapy; Tumor microenvironment.

Figure 1.. Tumor environment and its impact on tumor cells, immune cells, stroma cells, and chemo/immunotherapy

The tumor microenvironment (TME) is often characterized by low levels of nutrients and oxygen, acidic pH, and accumulation of oncometabolites. Low levels of nutrients and oxygen activate several growth and survival pathways such as Hif1a, MAPK, and mTOR. Additionally, a metabolic shift towards glycolysis and glutaminolysis leads to epigenetic reprogramming such as abnormal methylation and acetylation that support proliferation, metastasis and chemotherapy resistance. The TME supports immunosuppressive populations (MDSCs, Tregs, and M2-like macrophages), while anti-tumor immune cell populations (M1-like macrophages, NK cells, and effector T cells） develop an exhausted phenotype, resulting in immune evasion and poor response to immunotherapy. Metabolic reprogramming and secretion of immunosuppressive chemokines in CAFs and CAAs also contribute to both chemotherapy resistance and immunotherapy resistance.

Figure 2.. Nanotechnology to facilitate targeting of cancer metabolism

Anti-tumor immune cells compete for nutrients with tumor cells in the TME (①). Without proper targeting, immune cells would also be significantly affected by metabolic inhibition. By targeting tumor cells, nano-drug delivery systems localize metabolic inhibitors in tumor cells to inhibit metabolic pathways in cancer, reducing the undesired impact on immune cell populations (②). Restricting metabolic inhibition to tumor cells also helps to decrease the production of oncometabolites (③), and therefore minimize their impact on immune cells (④). Additionally, nano-drug delivery system allows maximizing the therapeutic dose and the synergistic effect between cytotoxicity agent and metabolic inhibitor (⑤).