Argonaute 2 drives resistance to immune checkpoint inhibitors in immunorefractory non-small cell lung cancer
Year: 2026
Type: article
Abstract: 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.
Source: PLoS Biology
Authors: Dario Pasquale Anobile, Layla Barbar, Emile Maucotel, Alexis Cornec, Valeria Manriquez, Wilfrid Richer, Jordan Denizeau, Christine Sedlik, Charlie Bories, Elodie Couderc, Renaud Leclere, Judith Sobas, Emeline Papillon, Rafael Mena Osuna, Jimena Tosello-Boari, Marianne Burbage, Eliane Piaggio, Enzo Z. Poirier
Institutions: Inserm, Université Paris Sciences et Lettres, Institut Curie
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,500
Funders: Equipex, European Commission, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, Conseil Régional, Île-de-France, Ligue Contre le Cancer, Institut National Du Cancer, Direction Générale de l’offre de Soins, Université de Recherche Paris Sciences et Lettres, Institut Curie, HORIZON EUROPE European Research Council
Awards: G128859847, G1435997383, G1554707310, Deciphering stem cell immunity, G2579310621, G2580753410, Paris Sciences et Lettres, G271172329, G3379613862, G3489752117, G3898041522, G3953683450, G4072984709, G4190806336, G449165211, G471331628, G5125889110, G534649664, G5665028823, G6062526893, Institut Curie EuReCa PhD Programme, G6759105742, G683439542, G705061367, G7240651115, G746701943, G782245399, G786270660, G7999552054, G8116744535, G8301460240, G8510727784, G8910691279, G937427620
OpenAlex ID: W7165124902