Residual tumor cells after insufficient radiofrequency ablation promote lung metastasis by educating CD177hiPAD4hi neutrophils

Radiofrequency ablation (RFA) has been one of the most promising local treatments for colorectal liver metastases. However, tumor progression after RFA still severely affects patient prognosis, and its molecular mechanisms remain to be further explored. Here, we show that heat-stressed residual tumor cells following insufficient RFA (iRFA) can lead to lung metastases. Specific Cd177hiPad4hi neutrophils are found as the main pro-tumor phenotype in iRFA conditions, and neutrophil extracellular traps are produced to accelerate lung metastasis via the MEK/ERK signaling pathway. Mechanistically, PPARγ-triglyceride (TG) synthesis in residual tumor cells activates the P38 signaling pathway and CXCL5 secretion, contributing to Cd177hiPad4hi neutrophil infiltration. Furthermore, the specific CD36hi-EM (epithelial-mesenchymal) - circulating tumor cells (CTCs) with activated lipid metabolism characteristics are found to assist in early identification of residual tumor cells. This study not only provides specific targets for improving the efficacy of iRFA but also realizes its early identification and intervention. A relatively high proportion of patients relapse following radiofrequency ablation. Here, authors show that neutrophils with high expression of CD177 and PAD4 promote progression of residual tumors after incomplete radiofrequency ablation via PPARγ-related lipid metabolism adaptation.