Modulating Glycolysis to Improve Cancer Therapy

Abstract

Cancer cells undergo metabolic reprogramming and switch to a 'glycolysis-dominant' metabolic profile to promote their survival and meet their requirements for energy and macromolecules. This phenomenon, also known as the 'Warburg effect,' provides a survival advantage to the cancer cells and make the tumor environment more pro-cancerous. Additionally, the increased glycolytic dependence also promotes chemo/radio resistance. A similar switch to a glycolytic metabolic profile is also shown by the immune cells in the tumor microenvironment, inducing a competition between the cancer cells and the tumor-infiltrating cells over nutrients. Several recent studies have shown that targeting the enhanced glycolysis in cancer cells is a promising strategy to make them more susceptible to treatment with other conventional treatment modalities, including chemotherapy, radiotherapy, hormonal therapy, immunotherapy, and photodynamic therapy. Although several targeting strategies have been developed and several of them are in different stages of pre-clinical and clinical evaluation, there is still a lack of effective strategies to specifically target cancer cell glycolysis to improve treatment efficacy. Herein, we have reviewed our current understanding of the role of metabolic reprogramming in cancer cells and how targeting this phenomenon could be a potential strategy to improve the efficacy of conventional cancer therapy.

Keywords: cancer metabolism; combination therapy; glycolysis.

Figure 1

Targeting glycolysis to improve cancer therapy. The cancer cells show enhanced dependency on glycolysis that may be targeted to improve the treatment efficacy of conventional cancer therapy modalities, including chemotherapy, radiotherapy, immunotherapy, hormonal therapy, and photodynamic therapy. Glycolysis metabolism can be potentially targeted by limiting glucose uptake (targeting glucose transporters), targeting glycolysis enzymes, targeting glutaminolysis, targeting lactate synthesis, targeting MCT, or targeting mitochondrial complexes. The increased glycolysis in the cancer cells increase the release of lactic acid to the tumor microenvironment, acidifying it and making it pro-cancer and immunosuppressive. The tumor-infiltrating immune cells also show a similar shift toward glucose metabolism increasing the competition for glucose in the tumor microenvironment. Modulating glycolysis in the immune cells can potentially improve immune therapy. This figure was created using the Biorender app.

Figure 2

Naïve T-cells relay on oxidative metabolism. After activation, the effector T-cells increase glycolysis to support their function. On antigen clearance, the effector T-cells enter a memory state. On antigen persistence, as with long-term tumor elimination, inhibitory receptors such as PD-1 and CTLA4 reprogram the T-cell metabolism leading to metabolic impairments. Exhausted T-cells show reduced glycolysis and glutaminolysis and dependence of fatty acid oxidation. The low levels of oxygen, high levels of lactate, and the high competition for glucose potentially contribute to T-cell dysfunction in the tumor microenvironment. The image was created using Biorender app.

Figure 3

The heme biosynthesis is connected with glucose and glutamine metabolism. Enhanced glycolysis and glutaminolysis in the cancer cell might contribute to the elevated rate of heme synthesis and the upregulation of several heme biosynthesis pathway enzymes in the cancers. Addition of exogenous 5-ALA bypasses the feedback inhibition of ALAS and increase the accumulation of protoporphyrin IX (PpIX) in the cancer cells. The elevated accumulation of PpIX is exploited for fluorescence-guided detection (photodynamic diagnosis) of cancers. Further, irradiating PpIX-accumulating cancer cells with light generated singlet oxygen and ROS that kills the cancer cell, with minimal damage to the surrounding tissue (photodynamic therapy; PDT). The interdependency of glucose metabolism and the heme synthesis pathways suggest that targeting glycolysis could enable the modulation of PpIX accumulation in the cancer cells. The image was created using Biorender app.