PSMC5 Orchestrates an Immunosuppressive Niche and Metastasis in Colorectal Cancer via SMURF1-Mediated K11-Linked Ubiquitination of METTL14.

Colorectal cancer (CRC) metastasis requires coordination between tumor-intrinsic programs and the surrounding microenvironment, yet how proteasomal regulation intersects with the epitranscriptome in this process remains unclear. Here, analyses of TCGA, GEO, and an institutional cohort of 146 CRC patients identified PSMC5 upregulation as associated with metastatic progression and poor prognosis. Mechanistically, PSMC5 promoted SMURF1-dependent K11-linked ubiquitination of METTL14 at K263, leading to METTL14 destabilization, global m⁶A remodeling, and activation of EMT-associated malignant phenotypes. Rescue experiments further supported METTL14 as a functional downstream effector of PSMC5. Integrative single-cell, spatial transcriptomic, and multiplex immunofluorescence analyses showed that PSMC5-high epithelial states were associated with spatially organized "regulatory islands," defined here as PSMC5-high epithelial nests with peripheral Treg and M2 enrichment together with relative CD8⁺ T-cell exclusion. In vivo, SMURF1 silencing restored METTL14 expression and attenuated PSMC5-driven tumor growth and lung metastasis. Collectively, these findings define a PSMC5/SMURF1/METTL14 axis that links proteasomal regulation to epitranscriptomic remodeling and metastatic progression in CRC, and identify this pathway as a candidate therapeutically actionable axis.