Targeting the LHX1-LDB1 Complex Restores STING-dependent Senescence Surveillance and Inhibits Head and Neck Cancer Progression.

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 co

SUBMITTER: Long M 

PROVIDER: S-EPMC12836506 | biostudies-literature | 2026

REPOSITORIES: biostudies-literature