TTC7B Activates the AKT–JKAMP Signaling Axis to Promote Tumor Progression in Head and Neck Cancer

ABSTRACT The tetratricopeptide repeat domain 7 ( TTC7 ) family, comprising the paralogs TTC7A and TTC7B , encodes scaffold proteins that are critical for membrane signaling and cellular homeostasis. Although mutations in TTC7 family have been implicated in immune and developmental disorders, their roles in cancer, particularly head and neck cancer (HNC), remain largely unexplored. In this study, we systematically analyzed the expression, prognostic relevance, and biological functions of TTC7B in HNC using transcriptomic data, immunohistochemistry on tissue microarrays, in vitro functional assays, and integrative bioinformatic approaches. Compared with TTC7A , TTC7B was markedly upregulated in HNC and associated with poor survival. In vitro assays confirmed that TTC7B promotes HNC cell migration and invasion. Among the potential co‐dependent molecules, JNK1‐associated membrane protein ( JKAMP) emerged as a significantly co‐expressed transcript, with TTC7B high / JKAMP high patients consistently exhibiting the poorest survival rates. Mechanistically, TTC7B activated AKT to upregulate JKAMP, thereby enhancing malignant phenotypes. Pharmacological inhibition of AKT abolished TTC7B‐induced phosphorylation of AKT and JKAMP expression, suppressing migration and invasion, whereas IGF‐1–mediated AKT activation restored JKAMP expression and rescued TTC7B‐knockdown phenotypes. Moreover, JKAMP silencing in TTC7B‐overexpressing cells markedly reduced migration and invasion, indicating the oncogenic TTC7B–AKT–JKAMP signaling axis. In parallel, miR‐183‐5p suppressed TTC7B–AKT–JKAMP signaling, suggesting a potential regulatory mechanism. High TTC7B expression also attenuated the survival advantage conferred by tumor‐infiltrating CD8⁺ T cells, suggesting that TTC7B may promote immunosuppressive tumor microenvironment. Collectively, our findings establish TTC7B as a novel oncogenic factor in HNC that promotes tumor progression through the TTC7B–AKT–JKAMP axis and immune modulation, highlighting its potential as a prognostic biomarker and therapeutic target for HNC.