CD8+ T-cell exhaustion: Impediment to triple-negative breast cancer (TNBC) immunotherapy

Abstract

CD8⁺ T-cell exhaustion has been identified as a significant contributor to immunosuppression and immune escape in triple-negative breast cancer (TNBC). Dysfunction due to cell exhaustion is characterized by reduced effector capacity and sustained expression of inhibitory receptors (IRs). The factors contributing to CD8⁺ T-cell exhaustion are multifaceted, encompassing external influences such as the upregulation of IRs, reduction of effector cytokines, and internal changes within the immune cell, including transcriptomic alterations, epigenetic landscape remodeling, and metabolomic shifts. The impact of the altered TNBC tumor microenvironment (TME) on Tex is also a critical consideration. The production of exhausted CD8⁺ T-cells (CD8⁺ Tex) is positively correlated with poor prognosis and reduced response rates to immunotherapy in TNBC patients, underscoring the urgent need for the development of novel TNBC immunotherapeutic strategies that target the mechanisms of CD8⁺ T-cell exhaustion. This review delineates the dynamic trajectory of CD8⁺ T-cell exhaustion development in TNBC, provides an update on the latest research advancements in understanding its pathogenesis, and offers insights into potential immunotherapeutic strategies.