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. 2024 Sep 12;13(1):2400429. doi: 10.1080/2162402X.2024.2400429

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© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.

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Figure 1. — Multiprong strategies to overcome CD38-mediated CD8 T cell dysfunction to enhance ICB responsiveness: through its hydrolase/NADase activity, CD38 degrades NAD to form ADPR/cADPR, a secondary messenger in cell signaling pathways. In CD38^hi CD8 T cells, cADPR regulates Ryr2 calcium channel activation, which elevates intracellular Ca2+ levels resulting in chronic activation of AKT. Such CD38-mediated RyR2-AKT activation causes downregulation of TCF1 and promotes terminal differentiation of CD8 T cells leading to the unresponsiveness to anti-PD1 therapy. Genetic or pharmacological inhibition of various targets within CD38- RyR2-AKT-TCF1 axis, restores antitumor activities of CD38^hi CD8 T cells and improves responsiveness to ICB. Created with BioRender.com.