Drug-tolerant persister cells in lymphoid malignancies: from mechanisms to therapeutic opportunities.

Therapy resistance and relapse remain major obstacles in the treatment of lymphoid malignancies. While the cancer stem cell (CSC) hypothesis has long served as a conceptual framework for understanding chemoresistance, evidence for its direct applicability in lymphoid malignancies is still limited. More recently, drug-tolerant persister (DTP) cells have emerged as an important model for exploring resistance mechanisms, offering complementary perspectives beyond the CSC paradigm. In this review, we summarize recent advances in the study of DTP cells in lymphoid malignancies, including their progression to drug-tolerant expanded persister (DTEP) cells. We discuss experimental models and methodological approaches for investigating DTP cells, as well as the underlying mechanisms of persistence and resistance, which encompass gene-regulatory changes, cell surface remodeling, and immune evasion strategies. Finally, we highlight potential therapeutic avenues such as targeting glycosylation-related pathways, exploiting immunotherapeutic glycopeptide targets, and implementing rational combination regimens. By integrating insights from DTP biology, this review aims to broaden current theories to therapy resistance in lymphoid malignancies and inform the development of innovative treatment strategies.