Background <p>Cisplatin-based concurrent chemotherapy is considered first-line treatment for advanced NSCLC. In this study, the role of ⁶⁸Ga-FAPI in visualizing chemotherapy resistance and the regulatory mechanisms which CAFs influence chemoresistance of NSCLC was evaluated.</p> Methods <p>The CAFs were isolated form fresh NSCLC tissue, and the expression of FAP was evaluated by qRT-PCR and western blotting. ⁶⁸Ga-FAPI micro-PET/CT was performed to visualize CAFs distribution and quantity in vivo. A cytokine array was conducted to analyze the secretion of HGF. The expression of LINC01123 was detected by overlapping high-throughput sequencing results with the analysis of the GEO database (GSE43493). Finally, the interaction between LINC01123 and β-catenin was assessed using RNA pull-down and RIP techniques.</p> Results <p>In this study, we employed ⁶⁸Ga-FAPI micro-PET/CT to quantify the number of CAFs and visualize the different uptake between cisplatin sensitive and resistant NSCLC xenograft models. The biological role of CAFs in cisplatin treatment for NSCLC was evaluated through functional experiments in vitro and in vivo. Functional assay demonstrated that CAFs secrete HGF which upregulates the expression of LINC01123 in NSCLC cells. LINC01123 directly binds to β-catenin and enhances its transcription activity. The activated HGF/LILNC01123/β-catenin signaling-mediated crosstalk between CAFs and tumor cells drives the chemoresistance of NSCLC.</p> Conclusions <p>Dysregulated activation of the HGF/LINC01123/β-catenin cascade represents a pivotal pathway through which CAFs interact with NSCLC cells, which enhancing the role of ⁶⁸Ga-FAPI to visualize chemotherapy resistance in patients.</p>