Simple SummaryAnti-PD1 therapy appears as one of the most promising anticancer therapy of recent years. Almost all patients will develop resistance over time. In this context, we have sought to identify resistant patients, in order to be able to propose a therapeutic solution. Our study has identified a circulating biomarker discriminating patients at risk of escaping PD1 therapy. This biomarker is the adenosine methylated form of the EVs/exosomal miR-125a-5p. To go further, IGSF11- and METTL3-based therapies have demonstrated in vitro efficiency, suggesting that these therapies could be used in anti-PD1 therapy-treated patients having high levels of EVs/exosomal adenosine methylated miR 125a-5p.AbstractBackground: Despite encouraging anti-tumour activity in lung cancer, anti-PD-1 therapy has encountered increasing resistance to treatment. Several companion diagnostic assays have been performed to identify patients who may benefit from this immunotherapy and to adapt this therapy in case of acquired resistance. Methods: A large panel of methods was used for the analysis of expression and methylation levels of miRNAs (qPCR, MemiRIP, …), protein/miRNA interactions (CLIP, oligo pull-down, …), and protein–protein interactions (CoIP) in cells and/or blood samples. Results: Our work highlights that the saturation of PD-1 by anti-PD1 therapies induces an immune escape phenomenon due to the overexpression of IGSF11 following adenosine methylation of miR-125a-5p. Mechanistically, we identify METTL3/KHDRBS3 and HuR as two crucial players in the methylation and the loss of the repressive function of this miRNA. Finally, our work shows that the adenosine methylation of miR-125a-5p is analyzable from EVs/exosomes from longitudinal blood samples and that such EVs/exosomes modulate the IGSF11/VSIG3 expression in lung cancer cells to promote an immune escape phenomenon. Conclusions: Our data provide a biomarker (m6A-miR-125a-5p level) and two therapeutic solutions (anti-IGSF11 antibody and METTL3 inhibitor) that could potentially address the anti-PD1 therapy failure in the context of precision and personalized medicine.