Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Simple Summary In a tumor context, antitumor immune cells mediate an inflammatory response after activating a metabolic switch to kill cancer cells. However, tumors develop strategies to avoid destruction. Cancer cells are able to modify the metabolic environment of the tumor by sequestering nutrients (e.g., glucose, tryptophan, arginine) and by producing toxic waste compounds (e.g., adenosine, lactate, kynurenine). This tumor environment promotes exhaustion of antitumor immune cells while driving the expansion of Tregs and the expression of immune checkpoints. Establishment of such an immunosuppressive tumor environment decreases treatment response of cancer patients to immunotherapy. Interestingly, immunometabolism knowledge allows new therapeutic strategies to increase antitumor immune response by targeting the metabolism of both cancer and immune cells to improve immunotherapy. Over the past decade, advances in cancer immunotherapy through PD1-PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.