The immunogenicity control axis: a multi-omics framework for integrating epigenetic, DNA damage response, and immune...

Immunotherapy has transformed cancer treatment, yet therapeutic responses remain heterogeneous and are incompletely explained by immune-centric biomarkers alone. We propose the Immunogenicity Control Axis (ICA), a testable multi-omics framework integrating three complementary dimensions of tumor state: epigenetic regulation, DNA damage response (DDR), and immune activity. The central hypothesis is that epigenetic permissiveness influences immune-relevant transcription and antigen presentation, while DDR-associated genomic processes contribute to antigenic variation; together, these tumor-intrinsic features interact with the immune state to shape tumor immune visibility. To make this hypothesis quantitatively testable, the ICA is operationalized through independently derived Epigenetic, DDR, and Immune scores that are standardized and integrated into a composite ICA Score. Using cervical cancer as an initial disease context, patient-derived TCGA-CESC analyses provide exploratory assessment of ICA-associated molecular states and prognostic relationships, while synthetic analyses are used separately to illustrate specific analytical procedures. The framework is further extended to perturbational analysis, in which CMap/LINCS transcriptional signatures and network information are used to prioritize candidate natural compounds predicted to oppose ICA-associated molecular states. These computational analyses are intended as hypothesis-generating operationalizations rather than biological or clinical validation. ICA therefore provides a falsifiable framework for testing whether coordinated epigenetic, DDR, and immune information captures tumor immunogenic variation beyond individual molecular dimensions and for prioritizing perturbational hypotheses for subsequent experimental validation.