Tumor-associated disruption of T cell receptor signaling: lessons across cancers with implications for CLL

In chronic lymphocytic leukemia (CLL), T cell dysfunction is a hallmark feature and includes impaired proliferation, reduced cytotoxicity, defective immunological synapse formation, and metabolic exhaustion. While these alterations have been well described, the underlying mechanisms remain incompletely understood. By contrast, in the field of solid tumor immunotherapy, extensive research has yielded detailed mechanistic insights into how tumors evade T cell immunity, particularly by interfering with T cell receptor (TCR) signaling at multiple levels. This review examines whether the mechanisms of T cell dysfunction uncovered in solid oncology can inform our understanding of T cell failure in CLL. By aligning TCR defects in CLL with insights from solid tumors, we identify mechanistic explanations for T cell failure in CLL that warrant further investigation. These include non-canonical checkpoint signaling, recruitment of inhibitory phosphatases, and impaired propagation of activation signals. Understanding these pathways may enable rational design of next-generation immunotherapies for CLL.