RESEARCHERS have identified distinct drug tolerant cell states in TNBC that persist after neoadjuvant chemotherapy, offering new insight into treatment resistance and metastatic progression in patients with residual disease.
Although combining immune checkpoint blockade with chemotherapy has improved outcomes in early triple negative breast cancer, a proportion of patients continue to experience poor long term outcomes following treatment. To better understand the biology underlying chemotherapy resistance, investigators generated a high-resolution single cell atlas using 129,433 cells from 14 patient derived xenograft models of triple negative breast cancer with residual disease following neoadjuvant chemotherapy.
Using unsupervised clustering techniques, researchers identified four transcriptionally distinct cancer cell states shared across the models. These states demonstrated enrichment of developmental, hypoxia, interferon signalling, chromosomal instability, and DNA damage related pathways. Investigators also characterised the regulatory networks associated with these populations and explored links with treatment response, metastatic progression, and survival outcomes.
Hypoxia Related TNBC Cells Persist After Treatment
Two of the identified cell states, linked to hypoxia and interferon signalling, shared transcriptional features associated with drug tolerant persister cells. The hypoxia related populations included both cycling and non-cycling cells and showed no association with mutation status, suggesting that resistance mechanisms may be driven through epigenetic rather than genetic pathways.
Validation across multiple independent triple negative breast cancer cohorts confirmed that the dysregulated pathways observed in residual disease were already present in chemotherapy naïve tumours. Researchers further demonstrated that these cell states persisted in distant metastatic disease and were associated with both prognosis and treatment response.
The findings suggest that neoadjuvant chemotherapy may selectively enrich resistant persister cell populations that survive treatment and contribute to disease recurrence or progression.
Epigenetic Target May Reduce Resistant Cell Emergence
Functional in vitro experiments highlighted a potential therapeutic strategy targeting these resistant populations. Investigators found that inhibition of the lysine demethylase KDM5B suppressed the emergence of drug tolerant persister cells, indicating that epigenetic modulation could help prevent resistance development in TNBC.
Researchers concluded that neoadjuvant therapy selects for epigenetically regulated hypoxia related drug tolerant persister cells that are maintained in metastatic disease and are associated with treatment response and prognosis. The data provide further evidence that resistant cell states may represent important therapeutic targets in triple negative breast cancer.
Reference
Zhang Y et al. Co-occurrence of transcriptionally distinct persister cell states underpins neoadjuvant therapy resistance in triple‑negative breast cancer. Genome Med. 2026; doi: 10.1186/s13073-026-01643-9.
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