Recent Advances in Nitric Oxide-Releasing Metallodrugs for Cancer Therapy

Nitric oxide (NO) is a highly versatile signaling molecule that plays dual, context-dependent roles in tumor biology: at low physiological concentrations, it promotes tumor progression, whereas at supraphysiological levels, it exerts potent cytotoxic effects. Harnessing this functional duality for therapeutic benefit requires precise spatiotemporal control over NO delivery. This review summarizes recent advances in transition metal-based platforms designed for controlled NO release in cancer therapy, encompassing both small molecule metallodrugs and micro to nanoscale delivery systems. We systematically examine key strategies for NO loading and stimulus-triggered release, including direct metal-NO coordination, integration of stimulus-responsive organic NO donors, and catalytic NO generation driven by intracellular redox cues or external stimuli such as light and ultrasound. Additionally, we highlight the emerging immunomodulatory functions of NO-releasing metallodrugs, particularly their ability to induce immunogenic cell death, reprogram immunosuppressive myeloid cells, and synergistically enhance immune checkpoint blockade. Finally, we critically assess current challenges and outline future directions toward the development of clinically translatable next-generation NO metallodrug systems with improved tumor targeting and pharmacokinetic profiles.