XPC restrains cancer stemness by modulating STAT1-SOX2 signaling in non-small cell lung cancer

Cancer stem cells (CSCs) drive tumor initiation, therapeutic resistance, and disease relapse, yet the molecular mechanisms sustaining CSC maintenance remain incompletely defined. Xeroderma pigmentosum complementation group C (XPC) is a core DNA damage recognition factor in nucleotide excision repair, and its loss is linked to cancer predisposition. Beyond its canonical role in genome maintenance, XPC has emerged as a transcriptional co-regulator capable of modulating gene expression. Here, we identify XPC as a critical suppressor of CSC phenotypes in non-small cell lung cancer (NSCLC). Genetic depletion of XPC enhances CSC self-renewal and tumor-initiating capacity, whereas inducible XPC expression restricts the CSC population. Transcriptomic and functional analyses reveal that XPC negatively regulates the stemness factor SOX2. Mechanistically, XPC selectively suppresses STAT1 activation by inhibiting phosphorylation at Tyr701, physically associates with STAT1 in the nucleus, and limits STAT1 recruitment to the SOX2 promoter. Loss of XPC results in elevated STAT1 signaling, increased SOX2 transcription, and CSC expansion. Notably, STAT1 signaling is highly activated in CSC-enriched populations and is required for CSC self-renewal. Collectively, these findings uncover a DNA repair-independent function of XPC mediated through a previously unrecognized XPC-STAT1-SOX2 axis, redefining XPC as a regulator of tumor cell plasticity and highlighting STAT1 signaling as a potential therapeutic vulnerability in XPC-deficient tumors.