Metabolic Regulation of CD8+T Cells: From Mechanism to Therapy

Significance: Cancer immunotherapy has yielded striking antitumor effects in many cancers, yet the proportion of benefited patients is still limited. As key mediators of tumor suppression, CD8⁺ T cells are crucial for cancer immunotherapy. It has been widely appreciated that the modulation of CD8⁺ T cell immunity could be an effective way to further improve the therapeutic benefit of immunotherapy. Recent Advances: Emerging evidence has underlined a close link between metabolism and immune functions, providing a metabolism-immune axis that is increasingly investigated for understanding CD8⁺ T cell regulation. On the other hand, growing findings have reported that tumors adopt multiple approaches to induce metabolic reprogramming of CD8⁺ T cells, leading to compromised immunotherapy. Critical Issues: CD8⁺ T cell metabolism in the tumor microenvironment (TME) is often adapted to diminish antitumor immune responses and thereby evade from immune surveillance. A better understanding of metabolic regulation of CD8⁺ T cells in the TME is believed to hold promise for opening a new therapeutic window to further improve the benefit of immunotherapy. We herein review the mechanistic understanding of how CD8⁺ T cell metabolism is reprogrammed in the TME, mainly focusing on the impact of nutrient availability and bioactive molecules secreted by surrounding cells. Future Directions: Future research should pay attention to tumor heterogeneity in the metabolic microenvironment and associated immune responses. It is also important to include the trending opinion of "precision medicine" in cancer immunotherapies to tailor metabolic interventions for individual patients in combination with immunotherapy treatments. Antioxid. Redox Signal. 37, 1234-1253.