Yao et al. developed an EGFR/HER2-targeting conjugate, the dual-target ligand-based lidamycin (DTLL), which prevents tumour proliferation in SMAD4/DPC4-deficient PDAC through ATK/mTOR blockade and impaired NF-κB function, and also restores SMAD4/DPC4 bioactivity, triggering downstream NF-κB regulation in SMAD4/DPC4-deficient tumours of signalling to overcome chemoresistance. Here, SMAD4 is linked to neoplasm.