Pan-cancer 8q24 amplification predicts primary immunotherapy resistance and therapeutic vulnerabilities

Immune checkpoint blockade has transformed cancer therapy, yet most patients do not respond and reliable predictive biomarkers are lacking. Amplification of chromosomal region 8q24.21 is recurrent across cancer types, but its role in anti-tumor immunity is unknown. Through pan-cancer profiling of 10,809 tumor samples and validation in five independent immunotherapy cohorts (over 800 patients), we show that 8q24 amplification occurs in approximately 10% of human cancers and promises an immune-depleted microenvironment with reduced T cell infiltration and impaired antigen presentation. 8q24 amplification robustly predicted primary immunotherapy resistance and poor survival. A composite score integrating 8q24 status, tumor mutational burden, and PD-L1 expression effectively identified non-responders. Prognosis-driven and cell-line screening revealed 8q24-specific therapeutic vulnerabilities, providing a framework for targeted combination strategies in this genomically defined patient subset.