Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer

Interferon-γ (IFN-γ) is conventionally recognized as an antitumor cytokine. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-γ in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-γ can induce cancer progression. The mechanisms underlying the controversial role of IFN-γ regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-γ in inducing tumor stemness in patients with a variety of cancer types. Mechanically, low-level IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-γ 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-γ both in vitro and in vivo. Our study first defines the role of low-level IFN-γ in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-γ expression in the TME.