Genetic Ablation and Multi-Omics Profiling Reveal CEP55 as a Key Driver of Tumorigenesis in Diverse Cancer Models.

CEP55, a centrosomal protein frequently overexpressed in multiple cancers, is implicated in regulation of genomic instability and PI3K/AKT pathway activation, yet its role in tumor progression and the tumor microenvironment remains incompletely defined. Here, we developed an inducible Cep55 knockout (KO) mouse model and complementary primary, immortalized, and transformed mouse embryonic fibroblast (MEF) systems and employ integrative multi-omics analyses to define CEP55-driven mechanisms and validated findings in human cancer datasets. Cep55 deletion is well tolerated in adult tissues but significantly delays tumor onset and progression in E1A/Ras-driven models and prolongs survival in PTEN-deficient cancer models. Mechanistically, spatial transcriptomic and proteomic analyses revealed that CEP55 regulates extracellular matrix (ECM) remodeling, integrin signaling, and cell adhesion pathways, AKT/ERK signaling and cellular stress responses. Importantly, loss of Cep55 also reprograms the tumor immune microenvironment, reducing tumor-supportive macrophage polarization and enhancing antigen-specific CD8+ T-cell responses in vitro. Collectively, these findings demonstrate that CEP55 is dispensable for adult tissue homeostasis but plays a critical role in tumor progression by coordinating oncogenic signaling, extracellular matrix dynamics, and tumor-immune interactions and highlight it as a potential therapeutic target in aggressive and immune-resistant cancers.