Repurposing BH3 mimetics to deplete tumour-infiltrating regulatory T cells and enhance anti-tumour immunity in non-small cell lung cancer
- Author(s)
- Yao, E; Weeden, CE; Chen, T; Marceaux, C; Rankin, L; Batey, D; Teh, CE; Gray, DH; Asselin-Labat, ML;
- Journal Title
- Cell Death & Differentiation
- Publication Type
- Jul 15
- Abstract
- Tumour-infiltrating FOXP3(+) regulatory T cells (Tregs) exert suppression of anti-tumour immunity in non-small cell lung cancer (NSCLC), contributing to poor prognosis and immunotherapy resistance. The BCL-2 family pro-survival protein, MCL-1, is a critical controller of lymphoid Treg viability, yet its role in tumour-infiltrating Tregs remains poorly defined. Here we find that tumour-infiltrating effector Tregs in human NSCLC exhibit an activation-associated shift in BCL-2 family pro-survival protein expression typified by elevated MCL-1 expression. Pharmacological inhibition of MCL-1 with the BH3 mimetic S63845 induced moderate apoptotic cell death in both human and murine tumour-infiltrating Tregs, coincident with transient enhancement of CD8⁺ T cell activity. Combined MCL-1 inhibition and anti-PD1 immunotherapy further reduced tumour-infiltrating effector Treg abundance and influenced CD8⁺ T cell dynamics, although these effects were not sufficient to extend long-term survival. Mechanistically, we found that IL-33 upregulated MCL-1 expression and was required to support activated tumour-infiltrating Tregs. These results establish MCL-1 as an important regulator for tumour-infiltrating Treg survival and highlight the potential of repurposing BH3 mimetics to modulate immune suppression in NSCLC.
- Publisher
- Springer Nature
- Research Division(s)
- Personalised Oncology; Blood Cells and Blood Cancer; Advanced Technology and Biology; Immunology
- PubMed ID
- 42457926
- Publisher's Version
- https://doi.org/10.1038/s41418-026-01820-8
- Open Access at Publisher's Site
https://doi.org/10.1038/s41418-026-01820-8- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-07-23 11:46:52
Last Modified: 2026-07-23 11:47:01