Clinically, low STK25 expression correlated with elevated CAFs marker levels and poor cetuximab response in CRC patients.<h4>Conclusions</h4>Our findings identified STK25 as a critical regulator of the NF-κB/AREG/EGFR axis in tumour-CAF communication and highlight its potential as a therapeutic target for overcoming CAF-induced cetuximab resistance in CRC.<h4>Key points</h4>STK25 deficiency enhanced CAF-mediated CRC growth via the NF-κB/AREG/EGFR axis. Here, STK25 is linked to neoplasm.