Pioneer round of translation factor CTIF regulates tumor immunity in drug-tolerant persister cells

Background: Tumor cell plasticity enables cancer cells to alter their phenotype through coordinated epigenetic, transcriptional, and translational changes. Drug-tolerant persister cells (DTPs) represent a key plastic state associated with therapy resistance and minimal residual disease (MRD). Newly synthesized mRNAs undergo a pioneer round of translation (PRT) for quality control, yet how PRT influences tumor plasticity and immune evasion remains unknown. We hypothesize that the PRT-associated initiation factor CTIF, a core component of CBP80-CBP20-dependent translation machinery, regulates the immunosuppressive phenotype of DTPs and contributes to MRD-associated immune escape. Methods: We integrated the bulk RNA-seq datasets across LUAD, BRCA, SKCM and COAD to define cross-cancer DTP transcriptional features. DTP models and isogenic CTIF-knockdown (KD) cells were established across multiple cancer types. We examined PRT-related factor expression, drug IC50, proliferation, and translational output via polysome profile and ribosome sequencing (Ribo-seq). Functional relevance of CTIF was evaluated in vivo using syngeneic immunocompetent and immunodeficient models. Results: Cross-cancer analyses revealed treatment-specific DTP signatures with convergence on shared pathways, including altered expression of CTIF and additional PRT-related factors. CTIF-KD had minimal effects on drug resistance or proliferation in vitro, but polysome profiling and Ribo-seq indicated altered ribosome translation landscape. Integrated RNA-seq and Ribo-seq demonstrated that CTIF-KD selectively upregulated immune-related transcripts at the translational level, suggesting a previously unrecognized role in immune modulation. In vivo, CTIF-KD did not affect tumor growth in immunodeficient mice but significantly impaired tumor progression in immunocompetent hosts, consistent with enhanced immune recognition. Conclusions: Our study uncovers a non-canonical, immune-regulatory role of CTIF. Although dispensable for proliferation and drug tolerance in vitro, CTIF is essential for tumor growth in vivo in an immune-dependent manner. We propose that CTIF shapes the tumor translatome to sustain immune evasion, and that targeting PRT, particularly CTIF, may offer a novel strategy to overcome immune suppression and eliminate MRD-associated persister states within the tumor immune microenvironment.