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

ABSTRACT

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-ß, 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.

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.