IFNs are vital signaling cytokines that orchestrate complex, system-wide immune defenses. While their therapeutic and biomarker potential is vast, traditional abundance-based proteomics is fundamentally insufficient to capture the intricate post-translational and conformational dynamics driving these specific biological responses. This study aimed to systematically characterize the distinct mechanisms of action across different IFN types using a multi-faceted proteomics approach, seeking to deconvolute the complex immune regulatory landscape and identify novel functional targets. Human myeloid cell lines (THP-1 and HL-60) were stimulated with IFN-α, -β, or -γ. Protein expression, thermal stability, and redox states were simultaneously measured using the novel PISA-REX proteomics methodology. The resulting orthogonal datasets were evaluated independently via network clustering and functional enrichment, and subsequently integrated using the multi-block DIABLO (sPLS-DA) framework. Independent facet analysis revealed nuanced, subtype-specific regulatory mechanisms completely undetected by standard expression profiling, including the unique reductive properties of IFN-γ and the differential stability regulation of non-canonical pathways. Multi-omics integration successfully deconvoluted the core global IFN response from these subtype-specific signatures. Alongside canonical targets, this approach highlighted uncharacterized regulatory behaviors in novel biomarkers, notably the differential stabilization of the MCT1/MCT4 lactate transport complex. Furthermore, untargeted site-specific screening captured a broad array of established redox switches and functional residues, validating the high-throughput discovery potential of the PISA-REX pipeline. These findings demonstrate that standard expression measurements are inadequate for capturing the nuances of interferon perturbations. Future system-wide target deconvolution and the mapping of immune signaling networks rely inherently on multi-faceted, structure-aware proteomics.