Flexible pressure sensors based on polymeric nanocomposites have attracted widespread attention owing to exceptional low-temperature fatigue tolerance, yet the damage evolution of the nano-filler/matrix interface is still unclear. Herein, we prepare Cu/MXene/multi-wall carbon nanotubes (MWCNTs)/thermoplastic polyurethane (TPU)/Cu and Cu/MXene/MWCNTs/carbon black (CB)/TPU/Cu pressure sensors using solution blending-casting method, and systematically investigate the influence of the nano-fillers/matrix interfacial friction damage on low-temperature bending fatigue of the sensor under cyclic bending. It is found that the sensing performance of the device with binary [MXene/MWCNTs] synergistic network decreases by 65 % with decreasing temperature from 20 down to − 40 °C under 20,000 bending cycles, while that of the sensor with ternary [MXene/MWCNTs/CB] synergistic network drops by only 14.9 %. For the ternary composites, owing to the introduction of CB particles, the synergistic lubrication effect among the nano-fillers and the nano-mechanical interlocking interface between the nano-fillers and the polymer can cooperatively enhance the anchorage of the nano-fillers to the TPU chains, and hence alleviating friction energy accumulation at the nano-fillers/polymer interface. Our work shows that the synergistic reinforcing strategy may be valuable for the development of ultra-flexible sensors with low-temperature fatigue resistant.