Abstract

Resistance to anti-PD-1 immunotherapy remains a critical challenge in colorectal cancer (CRC). However, the functional role of S100A14 in CRC remains controversial regarding its oncogenic status and impact on immunotherapy response. Here, integrating single-cell RNA sequencing and tissue microarray analysis, we definitively identify S100A14 as an oncogenic driver of immunotherapy resistance. High S100A14 expression correlates with poor prognosis and an immunosuppressive “cold” tumor phenotype. Mechanistically, S100A14 directly binds UPF1, a core nonsense-mediated mRNA decay (NMD) factor, promoting its ubiquitination-mediated degradation. This impairs the decay of non-canonical NF-κB transcripts (MAP3K14, NFKB2, RELB), causing constitutive pathway activation and PD-L1 upregulation. In co-culture assays, S100A14-overexpressing cells directly suppressed CD8+ T-cell cytotoxicity by downregulating GZMB and induced exhaustion via PD-1 upregulation. In syngeneic mouse models, S100A14 overexpression accelerated hepatic metastasis and conferred anti-PD-1 resistance by suppressing GZMB+ CD8+ T-cell infiltration and promoting Treg recruitment. Notably, restoring UPF1 expression reversed malignant phenotypes in vitro and rescued S100A14-mediated immune evasion in co-culture models. Collectively, we define the S100A14-UPF1-non-canonical NF-κB axis as a actionable mechanism driving immune evasion in CRC.