Prophylactic low-dose liver irradiation reprograms the pre-metastatic immune niche and suppresses NSCLC liver metastasis

Liver metastasis relies on the establishment of a pre-metastatic niche (PMN) before tumor cell seeding. Although low-dose irradiation can modulate local immune responses, whether prophylactic low-dose liver irradiation influences hepatic PMN formation and metastatic colonization remains unclear. We used a prophylactic low-dose liver irradiation strategy in mouse models of non-small cell lung cancer (NSCLC) liver metastasis to evaluate its effects on metastatic colonization and hepatic immune remodelling. Bulk RNA sequencing, single-cell RNA sequencing, and in vitro functional assays were performed to characterize irradiation-induced hepatocyte-monocyte signaling, and in vivo CXCL10 neutralization was used to assess its functional relevance. Prophylactic low-dose liver irradiation suppressed NSCLC liver metastasis and reshaped the hepatic immune microenvironment during PMN formation. A single 2 Gy dose showed the strongest antimetastatic effect. Mechanistically, 2 Gy irradiation induced hepatocyte-derived SAA1. SAA1 activated a TLR2–NF-κB/RELA-associated transcriptional program in inflammatory monocytes, leading to SLC7A11 upregulation, improved redox homeostasis, and increased CXCL10 secretion. SLC7A11 activity was required to sustain this chemokine-secretory phenotype. CXCL10 neutralization in vivo reduced CD8 + T-cell recruitment and attenuated the antimetastatic effect of low-dose irradiation. Prophylactic low-dose liver irradiation limits NSCLC liver metastasis and is associated with reprogramming of the PMN toward an anti-metastatic immune state. These findings link irradiation to metastatic niche immune remodeling and highlight the translational relevance of low-dose immune radiobiology in metastasis control.