Drug screening identifies small-molecule inhibitors of regulatory T cells

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Activation of mechanisms that allow cancer cells to evade the body's immune system is crucial for cancer development. A promising strategy in cancer treatment is, therefore, to target precisely these mechanisms that enable cancer cells to evade the immune system.

An important tumor immune evasion mechanism is the inhibition of immune cells in the tumor microenvironment (TME) by regulatory T cells (Tregs). Although the immunosuppressive function of Tregs in the TME is well documented and there is still an unmet need to modulate Treg activity, the development of small molecule drugs targeting Tregs for cancer therapy has been very limited.  

The key lineage-specific transcription factor FoxP3 plays a crucial role in regulating the expression of several genes required for important Treg functions, such as CD25, CTLA4, CD73, and CD39, suggesting it as a potential target for cancer immunotherapy. Small molecule inhibitors that indirectly affect FoxP3 up-regulation or activation to turn off Tregs, have been shown to boost anti-tumor immune responses in vitro. Still, validation in vivo has so far been unsuccessful due to low selectivity versus effector T cells.

In a recently published paper, Identification of a group of 9-amino-acridines that selectively down-regulate regulatory T cell functions through FoxP3, Qian Wei, MATRIX researcher in precision immune oncology, and her colleagues, explore the direct targeting of FoxP3 as a basis for new immuno therapies. High-throughput phenotypic screening of a drug repurposing library using human primary T cells, has identified the anti-malaria drug quinacrine dihydrochloride dehydrate (QDD) as a promising FoxP3 down-regulator. Furthermore, in silico searches based on the structure of quinacrine, testing of sub-libraries of analogs in vitro, and validation identified a subset of 9-amino-acridine that selectively blocked Treg suppressive functions. These molecules disturbed the DNA-binding activity of FoxP3, thereby inhibiting FoxP3-regulated downstream gene regulation.

The authors have demonstrated that this group of compounds selectively inhibits Tregs and boosts anti-tumor immunity both in patient samples and in a mouse tumor model. Thus, screening for small molecule inhibitors of FoxP3 seems to be a feasible approach to pursuing Treg-based immunotherapy, and Qian Wei, PI Kjetil Taskén and their colleagues here deliver tool compounds to explore Treg functions in anti-tumor immunity further.

“Our work demonstrated the feasibility of targeting FoxP3⁺ Tregs with small molecules from a drug-repurposing library screen and provided proof-of-concept that promising candidates can be validated. This enabled us to expand the high-throughput drug screen to identify more potential small molecule drugs targeting FoxP3 in Tregs with potential clinical application”, says Qian Wei, first author of the published paper and precision immune oncolog yresearcher in MATRIX WP1.

Kjetil Taskén, senior author of the publication, Head of the Cell Signaling and Immune Regulation Research Group at Institute for Cancer Research, OUH and MATRIX WP1 leader, says “I am very happy to finally see this first paper on our Treg targeting strategy out! There is more coming”.

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Identificationof a group of 9-amino-acridines that selectively down-regulate regulatory Tcell functions through FoxP3

Wei Q, FoynH, Landskron J, Wang S, Rye IH, Skånland S, Russnes HEG, Klaveness J, Ahmad Rand Taskén K (2025), iScience, DOI: https://doi.org/10.1016/j.isci.2025.11193

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