This study presents an integrative analysis identifying a 26-gene signature associated with myeloid-derived suppressor cells (MDSCs) in cancer, leveraging mass spectrometry proteomics data, RNA sequencing data and external datasets from lung and head and neck cancers. The genes within this signature were found to correlate positively with MDSC infiltration and negatively with neutrophil and CD8+ T cell presence in the tumor microenvironment. Clinically, this signature showed a significant association with reduced survival rates in metastatic melanoma patients treated with PD1 inhibitors, highlighting its potential as a prognostic biomarker in cancer therapy. This study enhances our understanding of MDSCs in oncology and opens new avenues for targeted therapeutic strategies against MDSC-mediated immunosuppression in the tumor microenvironment.