3535 - Exploring the Role of Off-Target Low-Dose Liver Irradiation in Modulating the Hepatic Pre-Metastatic Niche and Immunotherapy Response in Lung Cancer

Purpose/Objective(s):

This study aimed to evaluate the association between off-target low-dose liver irradiation during thoracic radiotherapy and liver metastasis–free survival (LMFS) in lung cancer patients, and to determine whether pre-metastatic low-dose liver irradiation suppresses liver metastasis by reprogramming the hepatic immune microenvironment.

Materials/Methods:

Between 2022 and 2025, 373 lung cancer patients with liver metastasis were screened to identify 69 patients who had received thoracic radiotherapy prior to the development of liver metastasis. The primary endpoint was liver metastasis–free survival (LMFS), defined as the time from completion of thoracic radiotherapy to radiographic liver metastasis, excluding extrahepatic progression. A murine pre-metastatic niche (PMN) model was established using in vivo imaging and image-guided radiotherapy. Bulk RNA-seq (n=20) and scRNA-seq (n=6) identified optimal immune-activating doses and radiotherapy-induced cross-cell communication networks. In vivo cell depletion validated the anti-metastatic role of key immune cells. Combined low-dose liver irradiation and anti–PD-1 therapy was evaluated in SCLC and NSCLC liver metastasis models.

Results:

In the overall cohort, the median LMFS was 5.4 months. Patients receiving sequential immune checkpoint blockade (ICB) after thoracic radiotherapy had significantly prolonged LMFS compared with those receiving other systemic therapies (6.8 vs 3.9 months; p < 0.0001), a trend consistent across both NSCLC and SCLC. Thoracic target dose was not associated with LMFS; however, among ICB-treated patients, a mean liver dose =1 Gy was associated with significantly longer LMFS than <1 Gy (8.0 vs 6.4 months; p = 0.0112). Multivariable Cox regression identified post-radiotherapy ICB as an independent predictor of LMFS, whereas low-dose liver irradiation alone was not, suggesting a synergistic interaction with immunotherapy. In murine models, 2 Gy low-dose liver irradiation delayed liver metastasis formation, reduced metastatic burden, and improved survival, accompanied by enhanced immune activation and increased CD4? and CD8? T-cell infiltration. Single-cell and cell–cell communication analyses demonstrated that low-dose liver irradiation during the PMN stage induced an interferon-? (IFN-?)–centered multicellular immune network, reprogramming the hepatic microenvironment toward an immune-activated, anti-metastatic phenotype dominated by resident effector populations, including CD8? TRM cells and Kupffer cells. Consistently, combined low-dose liver irradiation and anti–PD-1 therapy significantly reduced liver metastasis incidence and delayed metastatic onset in both SCLC and NSCLC models, whereas anti–PD-1 monotherapy failed to remodel the PMN.

Conclusion:

Off-target low-dose liver irradiation during thoracic radiotherapy prolongs LMFS by inducing an IFN-?–centered immune network that enhances immunotherapy efficacy.