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

Interferon-γ (IFN-γ) is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFN-γ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFN-γ can induce cancer progression, yet the mechanisms underlying the controversial role of IFN-γ in tumor development remain unclear. Here we reveal a dose-dependent effect of IFN-γ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of 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. This study unveils the role of low levels of IFN-γ in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFN-γ in the TME.