Abstract

Circular RNAs (circRNAs) play an important role in tumorigenesis induced by carbon nanotubes (CNTs) exposure, but the specific mechanism remains unclear. Here, we demonstrate for the first time that circTNIK promotes CNTs-induced malignant transformation by regulating the endoplasmic reticulum (ER) chaperone GRP78, thereby disrupting ER homeostasis and inhibiting type I interferon (IFN-I)-mediated antitumor immunity. Mechanistically, circTNIK interacts with GRP78 and interferes with its interaction with UPR sensors, thereby activating the ER stress response and promoting the transformation of cells toward a malignant phenotype. Meanwhile, circTNIK upregulates the expression of GRP78 and promotes its partial translocation into the nucleus. In the nucleus, GRP78 competitively binds to ID2, preventing its interaction with p65, a subunit of nuclear factor-κB (NF-κB), thereby inhibiting the phosphorylation of both NF-κB and IRF3, attenuating the IFN-I-mediated antitumor immune response and accelerating malignant transformation. Animal experiments showed that overexpression of circTNIK aggravated lung lesions in CNTs-exposed mice, accompanied by increased recruitment of M2 macrophages and decreased infiltration of CD8+ T cells. In clinical lung cancer tissue samples, circTNIK expression was positively correlated with GRP78 expression and negatively correlated with IFN-I signaling intensity, further supporting its oncogenic role in vivo. In summary, this study reveals that circTNIK plays a key role in CNTs-induced lung cancer development by regulating GRP78-mediated ER stress and IFN-I immunosuppression, providing a potential biomarker and therapeutic target for the early diagnosis and treatment of environmental-exposure-related lung cancer.