Argonaute 2 drives resistance to immune checkpoint inhibitors in immunorefractory non-small cell lung cancer.

One of the first-line treatments for advanced non-small cell lung cancer (NSCLC) are immune checkpoint inhibitors (ICI), which activate the antitumor immune response. Despite their success, ICI remain ineffective in many patients, highlighting the need for strategies to overcome resistance. Most efforts have focused on promoting immune cell infiltration into refractory tumors to improve ICI efficacy. In this work, we mobilize this approach by focusing on Argonaute 2 (Ago2), a pivotal member of the RNA interference pathway. Using two murine models of immunorefractory NSCLC, we demonstrate that tumoral Ago2 suppresses interferon signaling, leading to poor immunogenicity and failure of ICI therapy. Genetic deletion of Ago2 in cancer cells restores interferon signaling and supports immune infiltration of the tumor. Consequently, whereas wild-type tumors are resistant to ICI, tumors devoid of Ago2 become sensitive to treatment. In NSCLC patients treated with ICI, high Ago2 expression and a low interferon signature in tumors correlate with reduced survival. Ago2 is thus a driver of the immunorefractory phenotype observed in NSCLC and may represent a therapeutic target when aiming to sensitize patients to ICI.