摘要Background:The pentose-phosphate pathway(PPP)plays a vital role in cell growth and metabolic reprogramming.However,its role in human cancer remains unclear.Methods:We conducted a systematic analysis to investigate the complex and crucial roles of the PPP using multi-omics data from more than 10,000 samples across 33 cancer types sourced from multiple databases,including the Molecular Signature Databases,The Cancer Genome Atlas,and Cancer Single-cell State Atlas.Independent cohorts such as IMvigor210 and Liver Cancer-RIKEN,Japan Project from International Cancer Genome Consortium(ICGC-LIRI-JP).Results:PPP-related genes were upregulated in most cancers,a phenomenon possibly driven by copy number variation and DNA methylation.Single-cell analysis revealed significant tumor-promoting features of PPP.We developed a PPP activity score to quantify the overall expression of PPP-related genes.PPP activity scores were significantly correlated with multiple hallmark pathways,the tumor microenvironment,cancer stemness,and immune-related signatures.Drug analysis revealed that high PPP activity scores contributed to resistance to drug-targeting pathways,including PI3K/mTOR,RTK,and TP53 signaling.In addition,PPP activity scores are potential pre-dictors of immunotherapy outcomes.Prognostic analysis revealed that whereas individual PPP-related genes had varying effects on sur-vival,high PPP activity scores were generally associated with poor prognosis,particularly in liver cancer.Conclusions:This study underscores the critical molecular and clinical roles of the PPP in human cancers and highlights its potential as a promising target for cancer treatment.