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. 2024 Aug 4;15:6613. doi: 10.1038/s41467-024-50881-1

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© The Author(s) 2024

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

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Fig. 7 — Top panels illustrate an ARF6-dependent mechanism of TME remodelling that accelerates tumour development. ARF6 is activated by IFNγ in a positive feedback loop that diverts the IFNγ receptor away from the lysosome, back to the plasma membrane, augmenting tumourintrinsic, IFNγ-induced expression of checkpoint ligands, PD-L1 and CD80, which inhibit CD8+ T cells that synapse with tumour antigen-loaded MHC-I. ARF6 activation also enhances expression of IFNγ-induced IDO-1, which facilitates recruitment and/or activation of immunosuppressive regulatory T cells (Tregs) and polymorphonuclear-derived myeloid-derived suppressor (PMN-MDSC) cells. Loss of ARF6 diminishes IFNγ-dependent immune suppression, unleashes CD8+ T cell effector function, and restricts tumour development. Bottom panels illustrate the impact of tumour-intrinsic ARF6 on response to immune checkpoint blockade therapy (ICB). Tumours with relatively high ARF6 expression/activation are reliant on IFNγ-driven immune resistance and are vulnerable to ICB. In contrast, tumours with relatively low ARF6 expression/activation progress independent of IFNγ-induced checkpoints and are resistant to therapy.