Bioorthogonal pre-targeting alleviate the limitations of traditional nanomedicines in passive and active targeting delivery. However, the high selectivity of bioorthogonal pre-targeting depends on the high expression level of antigens in lesion sites, and there are very limited targets with sufficient overexpression. Herein, we propose a tumor heterogeneity-independent antigen-responsive nanocarrier utilizing bioorthogonal pre-targeting and click-activated self-immolative polymers for stimulus signal conversion and amplification. This approach comprises a tetrazine (Tz) conjugated with trastuzumab (T-Tz), and a bioorthogonally activatable nanocarrier CONP which self-assembled by isocyanide and polyethylene glycol-modified poly (thiocarbamate) (NC-PTC-PEG) and hydrogen sulfide (H