Spatially targeted metabolic phenotyping of MTAP-deficient cancer tissues reveals tumor-localized MTA accumulation and lipid remodeling

Homozygous loss of chromosome 9p21 is one of the most frequent genomic alterations in human cancer and is associated with poor prognosis and resistance to immune checkpoint therapy. Deletion of the metabolic gene encoding methylthioadenosine phosphorylase enzyme, as a part of 9p21 loss, results in accumulation of its substrate 5'-methylthioadenosine , impairs methionine salvage, and disrupts other cellular processes. However, the metabolic consequences of MTAP deletion in human tumor tissues remain poorly defined. Here, we have developed a multiplexed workflow centered on desorption electrospray ionization mass spectrometry imaging to resolve metabolic alterations associated with MTAP loss across genetically defined animal models and primary human cancer tissues. Integration of this approach with exome sequencing and RNA-FISH revealed a conserved, tumor-specific metabolic signature of MTAP deficiency marked by MTA accumulation and coordinated disruptions in methionine cycle, purine, and polyamine metabolism.