From paradox to target: IFN-β hijacks MEK signaling to drive a cell death-evading dormant phenotype in colorectal cancer.

BACKGROUND

The high clinical recurrence rate of colorectal cancer (CRC) is driven by the survival of residual tumor cells that evade therapy-induced death by entering a dormant state. While dormancy is a recognized mechanism of treatment resistance, the molecular drivers governing this "quiescent reservoir" and its associated vulnerabilities remain poorly characterized, limiting the development of strategies to eradicate these dormant seeds.

METHODS

We developed a COAD-specific Dormancy Score (CADS) derived from NMF analysis of ~ 69,000 single cells to quantify and identify a dormant subpopulation at single-cell resolution. Mechanistically, the IFN-β/cDC1 axis and its downstream MEK/ERK dependency were validated using a GFP-p27K- dormancy reporter system, spatial transcriptomics, and CRISPR/Cas9-mediated Ifnar1 knockdown. Finally, the synergistic efficacy of anti-PD-1 combined with MEK inhibition (Trametinib) was evaluated in orthotopic CRC mouse models.

RESULTS

The CADS effectively identified a distinct dormant subpopulation in CRC characterized by profound G0/G1 arrest, enhanced stemness, and multi-drug resistance. We uncovered a novel evasion mechanism mediated by the hijacking of IFN-β signaling. Conventionally recognized for its anti-proliferative roles, IFN-β signaling is exploited by surviving tumor cells to enter a deep quiescent state. This phenotype acts as a biological reservoir that fuels intratumoral heterogeneity and underpins the relapse of colorectal tumors by conferring resistance to conventional cytotoxic regimens. Effective anti-PD-1 therapy paradoxically enriches this dormant population via an enhanced IFN-β-conventional type 1 dendritic cell (cDC1) axis. Mechanistically, IFN-β-induced dormancy depends on MEK/ERK pathway activity, which sustains survival while suppressing apoptosis. This creates a synthetic lethal vulnerability: MEK inhibition (e.g., Trametinib) synergizes with IFN-β to re-sensitize dormant cells to apoptosis. Consequently, combining Trametinib with anti-PD-1 therapy overcomes this evasion mechanism, eliminates the dormant subpopulation, remodels the immune microenvironment, and shows strong synergistic efficacy in preclinical models.

CONCLUSION

Our work redefines an immune-cell death paradox, revealing how tumors exploit IFN-β to evade therapy. We propose CADS as a translational biomarker for identifying tumors reliant on this pathway and validate a mechanism-based combination therapy that selectively targets dormancy-associated death resistance, offering a promising strategy to improve CRC outcomes.