The molecular landscape of T cell exhaustion in the tumor microenvironment and reinvigoration strategies.

Immunotherapy has emerged as a promising therapeutic approach for cancer treatment by harnessing the immune system to target cancer cells. However, the efficacy of immunotherapy is hindered by the tumor microenvironment (TME), comprising regulatory T cells (Tregs), macrophages, myeloid-derived suppressor cells (MDSCs), neutrophils, soluble factors (TGF-β, IL-35, IL-10), and hypoxia. These components interact with inhibitory receptors (IRs) on T cells, leading to alterations in T cell transcriptomes, epigenomes, and metabolism, ultimately resulting in T cell exhaustion and compromising the effectiveness of immunotherapy. T cell exhaustion occurs in two phases: pre-exhaustion and exhaustion. Pre-exhausted T cells exhibit reversibility and distinct molecular properties compared to terminally exhausted T cells. Understanding these differences is crucial for designing effective interventions. This comprehensive review summarizes the characteristics of pre-exhausted and exhausted T cells and elucidates the influence of TME components on T cell activity, transcriptomes, epigenomes, and metabolism, ultimately driving T cell exhaustion in cancer. Additionally, potential intervention strategies for reversing exhaustion are discussed. By gaining insights into the mechanisms underlying T cell exhaustion and the impact of the TME, this review aims to inform the development of innovative approaches for combating T cell exhaustion and enhancing the efficacy of immunotherapy in cancer treatment. PLAIN LANGUAGE SUMMARY: The immune system normally attacks any external factor or abnormal cell in the body, however, sometimes abnormal cells such as cancerous cells can escape the immune system and form a tumor. A class of therapy known as immunotherapy relies on reinforcing the immune system in fighting cancerous cells. However, it cannot have a sustained effect because due to chronic exposure to cancerous cells, T cells, which are the pivotal cells in anti-cancer immunity, gradually lose their activity, a phenomenon known as T cell exhaustion. Exhausted T cells differ from normal T cells in metabolism, transcriptomes, and epigenomes and express different molecules, consequently leading to their dysfunction. By having a comprehensive knowledge of exhausted T cells properties and the factors that give rise to exhaustion, scientists can think of new strategies to make immunotherapy more robust. [ABSTRACT FROM AUTHOR]