TIGIT regulates CD8+T cell exhaustion via the PI3K/AKT-FOXO1-TOX axis in extrahepatic cholangiocarcinoma.

Abstract

Extrahepatic cholangiocarcinoma (ECCA) is an aggressive malignancy with poor prognosis and few treatment options, partly due to CD8+T cell exhaustion in the tumor microenvironment. The role of TIGIT in driving this process remains mechanistically unclear. Using patient-derived immunocompetent cultures (iPDCs), we show that TIGIT blockade in ECCA reverses exhaustion by downregulating TOX and restoring TCF-1. In mouse CD8+ T cells, transcriptomic analysis identifies the PI3K/AKT-FOXO1 axis as a critical mediator. Mechanistically, TIGIT suppresses AKT phosphorylation, leading to FOXO1 nuclear translocation, where FOXO1 directly binds the TOX promoter and activates its transcription. Together, these findings establish the TIGIT-PI3K/AKT-FOXO1-TOX axis as a core pathway driving CD8+T cell exhaustion in ECCA, filling a key mechanistic gap and offering new therapeutic targets for immunotherapy.