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Background Ancestral effects have been increasingly investigated over the years in efforts to reduce health disparities. Multi-omics analyses of large-scale datasets such as The Cancer Genome Atlas (TCGA) and MSK-IMPACT have demonstrated that different ancestral populations exhibit some population-specific molecular characteristics. The effects of ancestry on emerging therapy approaches such as chimeric antigen receptor (CAR) T cell therapy and proteolysis-targeting chimeras (PROTACs) therapy are also beginning to be appreciated. Although systematic multi-omics analysis revealed various ancestry-dependent molecular alterations, the effects of different molecular characteristics in diverse ancestries on cancer treatment outcomes remain to be fully elucidated. Therefore, a large-scale study evaluating the potential relations between multi-omics and clinical outcomes in different ancestral populations across cancer types is called for. The resulting data can provide insights into the effect of ancestry-associated disparities on the efficacy in anti-cancer treatments, leading to an improved understanding of health disparities.Methods In this study, we performed an integrated analysis of clinically actionable genes, imputed drug response, and immune features related to immune checkpoint blockade (ICB) therapy in in African (AFR), European (EUR), and East Asian (EAS) populations across 24 cancer types in TCGA dataset. We also validated our key findings in multiple independent cohorts from PubMed, NCBI-GEO and ClinicalTrials.gov., including multi-omics dataset and clinical trials.Results We identified potential differences in treatment response to targeted, chemo and immunotherapies between different ancestral populations. Further analysis of multiple independent cohorts, including multi-omics dataset and clinical trials, confirmed some of our key findings. These findings are made publicly available in a comprehensive web portal, Ancestral Differences of Efficacy in Cancers (ADEC; https://hanlaboratory.com/ADEC), to facilitate further investigation.Conclusions Our study provides a global overview of ancestry-associated differences in therapeutic efficacy, highlighting the importance of considering ancestry in anti-cancer therapies.