Specific imaging of the tumor microenvironment is critical for precise cancer diagnosis, yet conventional single-modal imaging techniques struggle to combine high sensitivity with high spatial resolution. This study designed and synthesized a cRGD peptide-targeted, nitroreductase (NTR)-responsive hemicyanine-¹⁹F dual-modal probe, Cy-F-cRGD. Through systematic screening of different fluorine-containing groups, we found that an ortho-difluoro structure induced a remarkable ¹⁹F chemical shift change (Δδ_F = 10.87). Concurrently, the hemicyanine unit exhibited an 80 nm red-shift in absorption and a 90-fold fluorescence enhancement, achieving an optical “off-on” signal switch. This work offers a new design strategy for developing intelligently responsive multimodal probes.