Subnuclear compartmentalization has emerged as a critical determinant of transcriptional homeostasis and cell-fate determination. The nucleolus scaffolds specialized heterochromatin, yet the mechanisms orchestrating its spatial assembly and therapeutic relevance remain elusive. Here we identify the nucleolar deubiquitinase OTUD4 as a key coordinator of heterochromatin architecture. We demonstrate that casein kinase II (CK2)-mediated phosphorylation serves as a molecular switch to activate OTUD4, which functions as a phospho-activated, K63-specific deubiquitinase. Crucially, we show that the spatial anchoring of H3K9me3-marked heterochromatin to the nucleolar surface is molecularly mandated by the K63-linked ubiquitination status of Nucleophosmin (NPM1) at the Lys27 (K27) residue. OTUD4-mediated deubiquitination of NPM1 K27 is indispensable for stabilizing the NPM1 pentameric scaffold, which in turn sequesters H3K9me3-marked domains at the nucleolar periphery. Disruption of the CK2–OTUD4–NPM1 axis triggers heterochromatin detachment, eliciting nucleolar stress and retroelement derepression. This epigenetic collapse activates cytosolic DNA-sensing pathways to potentiate tumor-intrinsic immunogenicity. Clinically, an OTUD4-nucleolus gene signature correlates with adverse survival and immunotherapy resistance. Together, these findings establish a phosphorylation–deubiquitination cascade to preserve heterochromatin topology and nominate spatial epigenetic targeting as a translational strategy to overcome immune evasion in refractory malignancies.