FLI1 promotes IFN-γ-induced kynurenine production to impair anti-tumor immunity (ChIP-Seq)

Nasopharyngeal carcinoma (NPC)-mediated immunosuppression within the tumor microenvironment (TME) frequently culminates in the failure of otherwise promising immunotherapies, underscoring the imperative to develop strategies to counteract the tumor's ability to foster an immunologically "cold" TME. In this study, we identify tumor-intrinsic FLI1 as a critical mediator in impairing T cell anti-tumor immunity through bioinformatic analysis. A mechanistic inquiry reveals that FLI1 orchestrates the expression of CBP and STAT1, facilitating chromatin accessibility and transcriptional activation of IDO1 in response to T cell-released IFN-γ. This regulatory cascade ultimately leads to augmented IDO1 expression, resulting in heightened synthesis of kynurenine (Kyn) in tumor cells. This, in turn, fosters CD8+ T cell exhaustion and regulatory T cell (Treg) differentiation, a process that redounds to the advantage of tumor cell survival. To elucidate the mechanism driving FLI1-mediated CD8+ T cell exhaustion, we conducted RNA sequencing (RNA-seq) on FLI1-KO and WT HK1 cells after co-incubation with activated CD8+ T cells.