Centromere protein M (CENPM) is a critical component of the constitutive centromere-associated network, playing a significant role in the assembly of kinetochores and the organization of chromosomes.1 Emerging evidence suggests that centromere protein family members contribute to cancer progression through multifaceted regulatory mechanisms,2,3 with CENPM overexpression implicated in tumor advancement through its oncogenic pathways.4 However, the biological implications and immune significance of CENPM in pan-cancer remain to be further understood. Through integrative multi-omics analysis of 33 cancer types, we revealed that CENPM is aberrantly overexpressed in 28 malignancies and serves as a robust prognostic predictor across multiplecancer types. Mechanistically, CENPM was observed to fuel genomic instability via synergistic interactions with tumor mutational burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) pathways, while concurrently shaping immunosuppressive microenvironments through myeloid-derived suppressor cell (MDSC) infiltration. Functional enrichment analyses further implicated CENPM in ribosome biogenesis and cell cycle regulation, bridging mitotic dysregulation to tumor progression. Critically, we demonstrate that CENPM operates as an immunological “switch” determining MDSC infiltration’s clinical impact. These findings reveal CENPM as both a prognostic indicator and a promising target for immunotherapy strategies across diverse malignancies.