Abstract
The senescence-associated secretory phenotype (SASP) exerts dual roles in tumor suppression and progression, yet how it is regulated in head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we identify LIM homeobox 1 (LHX1) as a key transcriptional suppressor of STING, whose downregulation enables evasion of SASP-mediated tumor surveillance. Notably, high LHX1 expression correlated with poor prognosis in HNSCC patients. Mechanistically, LHX1, in complex with LDB1, directly bound to the STING promoter to mediate transcriptional repression via the deposition of the repressive histone mark H3K9me3, thereby blocking SASP activation. Depletion of LHX1 restored STING-dependent SASP and impaired cancer stem cell self-renewal. Therapeutic disruption of the LHX1-LDB1 complex using engineered peptides re-activated STING signaling, induced SASP, and significantly suppressed tumor growth. In this study, we employed human and mouse-derived HNSCC cell lines, xenograft models, and clinical samples to assess the functional relevance of LHX1 in regulating SASP and tumor progression. Our findings reveal LHX1 as a master transcriptional repressor of STING-mediated senescence and highlight the therapeutic potential of targeting the LHX1-LDB1 axis to restore tumor-suppressive SASP in HNSCC.