carcinoma and pancreatic ductal adenocarcinoma and gastric cancer across two independent national nationwide cohorts. By integrating clinical pathological data, genomic co-alteration, survival outcome, and tumor microenvironment analysis, our work extends prior pre-clinical and limited clinical observations into a robust real-world clinical context. A key clinical implication of this study is the demonstration of MTAP loss is not only a genomic deletion, but is linked to a formation of immunosuppressive tumor microenvironment...
carcinoma and pancreatic ductal adenocarcinoma and gastric cancer across two independent national nationwide cohorts. By integrating clinical pathological data, genomic co-alteration, survival outcome, and tumor microenvironment analysis, our work extends prior pre-clinical and limited clinical observations into a robust real-world clinical context. A key clinical implication of this study is the demonstration of MTAP loss is not only a genomic deletion, but is linked to a formation of immunosuppressive tumor microenvironment. Our analyses support a dual-mechanistic model in which MTAP accumulation-mediated suppression of PRMT5 activity and co-deletion of the chromosome 9p21 type 1 interferon gene cluster jointly impair antitumor immunity. These alterations result in reduced CD4 and CD8 positive T cell infiltration and attenuated interferon signaling, thereby providing a biological explanation for observed resistance to immune checkpoint inhibitors in MTAP-deleted tumors. These findings have direct relevance to the ongoing therapeutic development targeting MTAP-deleted tumors. As PRMT5 and MAD2 inhibitors advance through early-phase clinical development, our data emphasize the importance of rational patient and tumor type selection, as well as the strategic incorporation of combination therapy. The cancer type-specific prevalence, prognostic impact, and immune context defined in this study offer a clinically meaningful framework for prioritizing indication and designing combination strategies. Importantly, our analysis also supports the concept that the immune resistance associated with MTAP loss may be therapeutically reversible. Recent clinical evidence demonstrating immune restoration through MTAP cooperative PRMT5 inhibition or reactivation of STING/IRF-3 axis using DFMO is strongly reinforced by our clinical and translational findings. Thus, MTAP loss should be viewed not only as a marker of prognosis or ICI resistance, but also as a biologically defining vulnerability that can be exploited through metabolic and epigenomic reprogramming. Collectively, this study positions MTAP status as an integrated biomarker with prognostic, predictive, and therapeutic relevance. Incorporation of MTAP status into clinical decision making and trial design may enable more precise selection of patients for emerging target agents and rational combination therapy. Ultimately, these insights have the potential to translate into more personalized and effective treatment strategies for patients with MTAP-deleted tumors.
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