Sonia Cinque, Yvessa Verheyden, Sara Adnane, Alessandro Marino, Sarah Hanache, Roberto Vendramin, Alessandro Cuomo, Joanna Poźniak, Álvaro Cortés Calabuig, Marcella Baldewijns, Sébastien P. Tabruyn, Oliver Bechter, Maria Francesca Baietti, Elisabetta Groaz, Tiziana Bonaldi, Eleonora Leucci
Gains of chromosome 12p11.21, encoding for the cancer-specific lncRNA LISRR, correlate with poor survival across different cancers. In melanoma, LISRR is upregulated in immunotherapy-resistant patients to contribute to the generation of drug-tolerant cells by activating an immune-suppressive translational program, affecting the synthesis of PD-L1 and of the glycocalyx. Accordingly, downregulation of LISRR initiates robust immune responses and resensitizes to immunotherapy ex vivo and in vivo. The use of glycans to evade immunity exhibits shared characteristics with the testis, where defects in the glycocalyx cause infertility. Mechanistically, we showed that LISRR affects the ribosome core composition and recruits deleted in azoospermia-associated protein 1 to polysomes to prime the integrated stress response. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based strategy to overcome resistance to immune checkpoint blockade.