Time-Series Multi-Omics Identifies ZG16 as a Prognostic Immunoregulatory Driver of Colitis-associated Colon Cancer Development and Checkpoint Blockade Response

Chronic inflammation is a known driver of colitis-associated cancer (CAC), yet the trajectory of immune suppression and its reversibility remain poorly defined. Here, we performed a time-series multi-omics analysis combining paired transcriptomic and proteomic profiling, flow cytometry, and cytokine measurements in an AOM/DSS-induced model, further supported by single-cell transcriptomic and epigenomic datasets. This roadmap delineates a stepwise progressive evolution of immune suppression, capturing coordinated changes in immune cell composition, cytokine dynamics, and inflammation-associated mutagenesis throughout CAC progression. We identified ZG16 as a previously undervalued immune modulator that is progressively downregulated during CAC and CRC development. Analysis of CRC cohorts in the TCGA database confirmed that ZG16 loss correlates with PD-L1 upregulation, suppression of T cell costimulatory/proliferative programs, and both poor prognosis and resistance to immunotherapy. Functionally, ZG16 suppresses PD-L1 expression and promotes CD8+ T/NK cell infiltration, thereby reshaping the tumor immune microenvironment. In both inflammation-driven and syngeneic tumor models, recombinant ZG16 reduces tumor burden and enhances the efficacy of PD-1 blockade. These findings position ZG16 as a rheostat-like immunoregulatory factor and translationally relevant biomarker in inflammation-driven cancers.