Nitric Oxide in Cancer: Mechanisms, Dual Role, and Therapeutic Strategies

ABSTRACT

Nitric oxide (NO) is an endogenous gasotransmitter that influences cancer progression in a concentration‐dependent manner, acting as either a tumor promoter or suppressor. Although this dual role is recognized, an integrated framework systematically linking its molecular mechanisms, immunomodulatory functions, and therapeutic translation is lacking, limiting rational design of NO‐based anticancer interventions. This review analyzes the molecular basis of the concentration‐dependent biphasic effects of NO, spanning canonical soluble guanylate cyclase‐cyclic guanosine monophosphate (cGMP) signaling, protein S‐nitrosylation (SNO), and peroxynitrite‐driven nitrosative stress. It then examines how these signaling pathways drive the direct effects of NO on tumor cell proliferation, metabolism, angiogenesis, and therapy resistance. It further delineates how these effects, together with NO‐mediated immunomodulation, define a dual role that encompasses both tumor cell‐intrinsic processes and antitumor immunity across innate and adaptive compartments. The therapeutic translation of these mechanistic insights is examined through NO donor chemistry and the integration of such donors into stimulus‐responsive delivery platforms, molecular conjugates, and combination regimens pairing NO with chemotherapy, radiotherapy, and immunotherapy. By connecting fundamental NO biology with emerging therapeutic strategies, this review offers an integrated framework to guide development of spatiotemporally controlled NO‐based interventions and identifies translational bottlenecks requiring resolution for clinical application, including targeted delivery, controlled release kinetics, and context‐dependent therapeutic windows.