T cell senescence in the tumor microenvironment

T cell senescence occurs in the TME, affecting cancer prognosis and immunotherapy efficacy. The TME induces T cell senescence through multiple pathways, including persistent stimulation by tumor-associated antigens, metabolic pathway alterations, activation of chronic inflammatory responses, proliferation of immunosuppressive cells, and T cell damage caused by tumor radiotherapy and chemotherapy. Senescent T cells exhibit characteristics such as genomic instability, protein imbalance, functional subgroup distribution and proportion imbalance, mitochondrial dysfunction with metabolic disorders, and epigenetic changes. Additionally, in the TME, crosstalk between senescent T cells and other immune cells (such as myeloid-derived suppressor cells, tumor-associated macrophages, dendritic cells) further exacerbates the immunosuppressive TME, and these interactions also impair T cells' ability to recognize and monitor tumor antigens.

The presence of senescent T cells is often associated with poor prognosis and reduced immunotherapy efficacy. In many tumor models, tumor-infiltrating lymphocytes show increased DNA damage and elevated SA-β-gal levels due to tumor progression, indicating that the TME contributes to driving T cell senescence and may lead to weakened immune checkpoint inhibitors (ICIs) outcomes. Evidence suggests that CD28 signaling is a key intermediary limiting T cell responsiveness in anti-PD-1/PD-L1 therapy. Furthermore, incorporating immune senescence biomarkers may become predictive factors for ICI efficacy. Additionally, T cell senescence also weakens the effectiveness of CAR-T cell therapy and cancer vaccines, and is even associated with immune-related adverse events. Therefore, breaking the immune senescence state in cancer patients is crucial for maintaining effective immune function after treatment.

This review systematically summarizes pathways that can improve T cell senescence states, including targeting senescence-associated key genes, regulating cell-cell interactions, intervening in cellular metabolism, modulating hormonal axis feedback, and protecting thymic function. Additionally, the review clarifies the differences between T cell senescence, exhaustion, and anergy, discusses the importance of precisely regulating immune senescence to avoid excessive or broad interventions that might drive tumor cell proliferation and invasion, proposes that accumulation of senescent unconventional T cells may also alter the tumor immune microenvironment, and explains the key role of current single-cell transcriptomics and cell trajectory modeling in locating T cell heterogeneity states.