Anti-trapping scaffold protein: significance in cancer cell innate immune signaling and opportunities for immunotherapy.

X-ray repair cross-complementing protein 1 (XRCC1) is a scaffold protein that functions as a molecular hub, serving as a platform for the recruitment and interaction of multiple DNA repair proteins to coordinate and facilitate multistep DNA repair processes. Furthermore, it acts as an antitrapping protein, ensuring the timely release of DNA repair proteins to prevent genotoxicity. XRCC1 participates in single-strand break repair (SSBR) pathways and has also been implicated in other DNA repair pathways. Preclinical studies have shown that XRCC1 deficiency delays SSB rejoining, induces mutations, and results in elevated levels of sister chromatid exchanges, a hallmark of genomic instability. XRCC1 deficiency results in hypersensitivity to ionizing radiation and chemotherapeutics. Analyses of the Cancer Genome Atlas (TCGA) datasets have revealed that approximately 30% of tumors exhibit low XRCC1 expression. Recently, Shahi et al. demonstrated that XRCC1 deficiency combined with pharmacological inhibition of Ataxia-Telangiectasia Mutated (ATM) induces mitotic failure, resulting in the accumulation of cytosolic DNA and activation of cancer cell-intrinsic innate immune signaling. Notably, this response was associated with increased PD-L1 expression, which may contribute to adaptive immune resistance. Collectively, these findings suggest that XRCC1 deficiency can promote cancer-cell-intrinsic molecular features associated with innate immune activation. This may represent a therapeutic vulnerability that warrants further evaluation in gastric cancer, particularly in studies combining DNA damage response (DDR) inhibition with immunotherapy.