MORC2 defines replication licensing -associated proliferative programs and an immunosuppressive microenvironment in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with poor clinical outcomes, substantial immune suppression, and limited molecular biomarkers for patient stratification. Microrchidia family CW-type zinc finger 2 (MORC2) is a chromatin-associated ATPase involved in genome maintenance and transcriptional regulation, but its biological and clinical relevance in OSCC remains incompletely understood. MORC2 expression, prognostic relevance, pathway associations, and immune features were evaluated using The Cancer Genome Atlas OSCC cohort and three independent Gene Expression Omnibus cohorts. Single-cell RNA sequencing was used to define the cellular distribution of MORC2, while immune deconvolution and transcriptome-based drug-response prediction were used to characterize its tumor microenvironmental and pharmacologic associations. Network-based virtual knockout analysis was performed to estimate MORC2-dependent transcriptional changes. Associations between MORC2 and replication-licensing and genome-maintenance programs were evaluated across multiple cohorts. CRISPR/Cas9-mediated MORC2 disruption in CAL27 cells was used for functional validation. MORC2 was consistently upregulated in OSCC and was associated with poorer overall survival. MORC2-high tumors showed enhanced replication licensing, mitotic, MYC, and cell-cycle programs, whereas MORC2-low tumors exhibited stronger immune and inflammatory signatures. Higher MORC2 expression was also associated with reduced CD8 + T-cell infiltration and lower cytolytic activity and tumor inflammation scores. Single-cell analyses localized MORC2 predominantly to malignant epithelial cells and linked its expression to genome-maintenance and proliferative states. Across independent cohorts, MORC2 was positively associated with replication-licensing and mitotic genes, particularly the MCM2/MCM7/FOXM1-related program. Consistent with these computational findings, MORC2 disruption reduced CAL27 cell proliferation, decreased the expression of replication-associated genes, and increased cisplatin-induced γH2AX accumulation. MORC2 is associated with a replication-licensing-active, proliferative, and immune-suppressed OSCC phenotype linked to adverse clinical outcomes. These findings support MORC2 as a candidate biomarker and provide a rationale for further mechanistic and preclinical evaluation of MORC2-associated vulnerabilities in OSCC.