Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small Cell Lung Cancer

IFN gamma is conventionally recognized as an inflammatory cytokine that plays a central role in antitumorimmunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFN gamma in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFN gamma can induce cancer progression, yet the mechanisms underlying the controversial role of IFN gamma in tumor development remain unclear. Here, we reveal a dose-dependent effect of IFN gamma in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFN gamma endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of IFN gamma activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFN gamma both in vitro and in vivo. This study unveils the role of low levels of IFN gamma in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFN gamma in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with lowexpression of IFN gamma in theTME. Significance: These findings reveal the dose-dependent effect of IFN gamma in inducing tumor stemness and elucidate the distinct molecular mechanisms activated by IFN gamma in a dose-dependent manner.