The role of nitric oxide in inflammation, tumor microenvironment, and cancer therapy

Nitric oxide (NO) is a widespread signaling molecule which has far-reaching effects in cellular physiology and pathophysiology, especially in cancer biology. Its actions are concentration-dependent where low concentrations facilitate tumor development and high concentrations cause cytotoxicity. NO alters several cancer hallmarks, affecting the initiation, progression, immune evasion, and therapeutic responses of tumors via cGMP-dependent and -independent pathways. Various cell types in the tumor microenvironment (TME) produce NO in a concentration gradient creating a strong concentration gradient that forms the immune landscape. NO mediates immunosuppression through the regulation of tumor-associated macrophage, myeloid-derived suppressor cell, T cells, and natural killer cells. It also controls angiogenesis and normalization of the vasculature via the VEGF-NO axis. Moreover, NO effects epithelial-mesenchymal transition and metastasis concentration-dependently. Notably, NO exists in a complex interaction with gasotransmitters, and it interacts with hydrogen sulfide and carbon monoxide in crosstalk to control cancer biology. Therapeutic interventions that focus on NO e.g., NO donors, iNOS-inhibitors and nanodelivery systems have been promising in preclinical practice. Nevertheless, clinical translation is complicated by the fact that the concentrations of intratumoral NO have to be tightly controlled, safety issues exist, and there are not many biomarkers of patient stratification. Integration of NO-based therapies with immunotherapy and precision medicine approaches holds promise for enhancing treatment outcomes. Continued research spanning chemical, biological, and clinical domains is crucial for unlocking the full therapeutic potential of NO in cancer. • Nitric oxide exerts dual, context-dependent effects on tumor growth and therapy response. • Novel insights into NO crosstalk with gasotransmitters and impact on cancer progression. • NO-based nanodelivery and gene-targeting strategies show enhanced anticancer efficacy. • Integration of NO modulation with immunotherapy and precision medicine is emphasized. • AI-driven prediction models are proposed to optimize NO-based cancer treatment outcomes.