Chromosomal region 9p21 is the most common homozygously deleted region in cancer and this has been attributed to the loss of the tumour suppressor genes CDKNA2 and CDKN2B, which are contained in this region. However, the 9p21 locus also contains MTAP, and this study shows that it is loss of MTAP (and not CDKNA2) that impairs the efficacy of immune checkpoint blockade (ICB) therapy in patients with melanoma and urothelial cancer with 9p21 deletion. Loss of MTAP causes accumulation of its substrate methylthioadenosine (MTA) in the extracellular space, and the authors show that MTA impairs T cell proliferation and function due to adenosine receptor agonism and inhibition of the arginine methyltransferase PRMT5. Notably, administration of MTA-hydrolysing enzymes, such as pegylated-MTAP, to mice with MTAP-deficient tumours reduced tumour growth and enhanced ICB efficacy in a CD8+ T cell-dependent manner. Therefore, combination therapy with MTAP and ICB could be an effective treatment for MTAP-deficient cancers.