Abstract 6538: A phase-separation mechanism underlying PD-1-mediated T-cell inhibition via Shp2 condensation

Abstract Microcluster formation is a hallmark of PD1 engagement, but its physical basis and functional impact have remained unclear. We show that ligand-bound PD1 triggers Shp2 self-association and liquid liquid phase separation, generating dynamic condensates whose liquidity depends on Shp2 catalytic activity. Mutations that disrupt Shp2 self-association weaken PD1 microclusters and reduce inhibitory signaling. These findings identify Shp2 phase separation as a fundamental organizing mechanism of the PD1 pathway, linking enzymatic activation, substrate selectivity, and higher-order assembly to suppress T cell responses. This work reveals a biophysical mechanism of PD1-mediated immune regulation with implications for improving checkpoint blockade therapies. Citation Format: Takeya Masubuchi, George Wen, Xiaoxian Song, Haian Shao, Enfu Hui. A phase-separation mechanism underlying PD-1-mediated T-cell inhibition via Shp2 condensation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6538.