T Cell Metabolism in Cancer Immunotherapy

Abstract

Immune checkpoint therapies aiming to enhance T cell responses have revolutionized cancer immunotherapy. However, although a small fraction of patients develops durable anti-tumor responses, the majority of patients display only transient responses, underlying the need for finding auxiliary approaches. Tumor microenvironment poses a major metabolic barrier to efficient anti-tumor T cell activity. As it is now well accepted that metabolism regulates T cell fate and function, harnessing metabolism may be a new strategy to potentiate T cell-based immunotherapies.

Keywords: ROS; T cell differentiation; T cell memory; adoptive cell therapy; cancer immunotherapy; glycolysis; immunometabolism; mitochondria.

Figure 1.. Mitochondrial metabolism supports T cell responses.

(A) Metabolic states of naïve, effector and memory T cells. (B) Dysfunctional metabolism in exhausted TILs with loss of mitochondrial fitness. Potential molecular targets to be activated or overexpressed to reinvigorate mitochondrial metabolism and to enhance anti-tumor function.

Figure 2.. Reactive oxygen species (ROS) impact on T cell activation.

T cell receptor (TCR) signaling regulates ROS production by inducing distinct pathways, including phosphorylation of MAPKs cascade, activation of the proximal Duox1 and increase in protein kinase C (PKC)-dependent activation of NADPH oxidase. Co-stimulatory signaling through CD28 activates the PI3K pathway, which generates ROS in the conversion of arachidonic acid intermediates. Moderate levels of superoxide radical (O2^•−) and hydrogen peroxide (H₂O₂) enhance IL-2 transcription, through NFAT nuclear localization, promoting T cell proliferation and activation. ROS induce Nrf2 translocation to the nucleus to regulate antioxidant response element (ARE)-dependent genes. Excessive ROS production results in activation-induced cell death (AICD) or ferroptosis.

Figure 3.. Metabolic balance of T cell function and differentiation.

Glycolysis, OXPHOS and FAO are tightly connected with ROS metabolism. TCR signaling simultaneously increases ROS levels and antioxidant responses. Modulating T cell metabolism alters ROS production and redox state with distinct effects on T cell activation, anergy and apoptosis, while antioxidant response (AR) halts T cell responses. ROS levels that exceed the protective capacity of antioxidant response may result in T cell hyperactivation and AICD or ferroptosis associated with cell contraction. Moderate ROS levels in turn are associated with T cell longevity and memory differentiation. Low ROS response levels are associated with T cell hypo-responsiveness and exhaustion.