Enhanced anti-tumour immunity by the Runx3R122C variant through inducing effector TEXprog development.

The efficacy of immune checkpoint blockade (ICB) relies on CD8⁺ stem/progenitor-exhausted T cells (TEXprog), which give rise to tumour-clearing effector T cells. However, poor responses to ICB and CAR-T therapies are often due to the accumulation of terminally exhausted T cells (TEXterm). Here, we show that the Runx3R122C mis-sense variant suppresses TEXterm differentiation via impairing Runx3-Nfil3 interactions, reducing expression of TEXterm genes Tim-3 and Prdm1. Furthermore, Runx3R122C variant promotes differentiation of novel subtype of TEXprog that possesses both stemness and effector signatures. Anti-tumour effects by such hybrid effector TEXprog are further amplified by ICB. Incorporation of Runx3R122C variant into CD19-CAR-T cells boosts their function and ICB responsiveness. Together with enhanced Natural Killer-mediated anti-tumour responses by Runx3R122C variant, our findings offer novel strategies to anti-cancer immunotherapy. Effects of Runx3-R122C on naïve and TCR-activated CD8 T cells