ABSTRACT Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behaviour only partially rescue the F508del-CFTR folding and trafficking defect observed in cystic fibrosis. Here, we describe novel, uniquely effective, macrocyclic CFTR correctors that were additive to the known corrector types, thus exerting a new, complementary “type-IV” corrector mechanism. Macrocycles achieved wildtype-like folding efficiency of F508del-CFTR at the endoplasmic reticulum and normalized CFTR currents in reconstituted patient-derived bronchial epithelium. Using photo-activatable macrocycles, docking studies and site-directed mutagenesis a highly probable binding site and pose for type-IV correctors was identified in a cavity between lasso helix-1 (Lh1) and transmembrane helix-1 of membrane spanning domain-1 (MSD1), distinct from the known corrector binding sites. Since only F508del-CFTR fragments spanning from Lh1 until MSD2 responded to type-IV correctors, these likely promote co-translational assembly of Lh1, MSD1, and MSD2. Remarkably, previously corrector-resistant CFTR folding mutations were also robustly rescued, suggesting substantial therapeutic potential for this novel type-IV corrector mechanism. Teaser A novel type of macrocyclic CFTR corrector with new binding site, complementary mode of action and unique folding / trafficking efficacy is described.