BCL11B predetermines a persister state in breast cancer that is reversed by TNFα

The frequent development of chemoresistance in cancer presents a major clinical challenge, yet the underlying causes of heterogeneous drug responses remain largely elusive. Here, we systematically assessed the cellular differentiation status of human breast cancer cells using single-cell atlases and identified a distinct population of immature basal-like cancer cells marked by BCL11B . Notably, higher levels of BCL11B + cancer cells are significantly associated with early relapse in patients with breast cancer who received chemotherapy. Functioning as a central regulator, B-cell lymphoma/leukemia 11B (BCL11B) delineates an immature cell state that preferentially transitions to a drug-resistant persister state during treatment through multiple preexisting and adaptive drug resistance programs. The cytokine tumor necrosis factor–α (TNFα) is revealed as a natural inhibitor of BCL11B and can directly reverse the emergence of chemoresistant persister cells. Therefore, we identify BCL11B as an unappreciated predeterminant of drug response and a therapeutic target for a subset of patients with breast cancer at high risk of developing chemoresistance.