The cancer-specific lncRNA LISR customizes ribosomes to suppress anti-tumour immunity
Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, resistance mechanisms limit its clinical benefit. Here we characterise LISRR, a cancer-specific lncRNA highly expressed in melanoma patients refractory to ICB. In cells undergoing (therapeutic) stress, LISRR recruits DAZAP1 (Deleted in AZoospermia Associated Protein 1) to polysomes and drives the assembly of a subset of ribosomes at the endoplasmic reticulum, directing the synthesis of an immunosuppressive translatome. This includes the immune checkpoint PD-L1 and the enzymes necessary for building the glycocalyx, the sugar coat surrounding the cells. Notably, proper glycocalyx assembly is required for spermatozoa immune evasion during fertilization. Accordingly, targeting LISRR activates immune responses and re-sensitizes to ICB in co-culture models, ex vivo in patient explants, and in vivo in humanized patient-derived models. Our study reveals the contribution of lncRNAs to the generation of cancer-specific ribosomes and identifies an RNA-based cancer-specific strategy to overcome intrinsic resistance to ICB.