An in-depth investigation into the role of NO factor in the dynamic immune microenvironment of cervical cancer
Year: 2026
Type: article
Abstract: Nitric oxide (NO) exhibits a concentration-dependent dual role within the microenvironment of cervical cancer. This review provides a systematic exploration of the multifaceted regulatory mechanisms of NO in HPV-associated cervical cancer. The E6 and E7 oncoproteins of high-risk HPV notably enhance the expression of inducible nitric oxide synthase (iNOS/NOS2) through various mechanisms, including epigenetic modifications (such as DNMT3B-mediated hypermethylation of the NOSIP promoter and H3K27ac-enhanced iNOS transcription), post-transcriptional modifications, and metabolic reprogramming (involving pathways such as hypoxia/HIF-1α and lactate/LDHA-YAP). NO is primarily produced by tumor cells, M2-type tumor-associated macrophages (TAMs), endothelial cells, and cancer-associated fibroblasts (CAFs), resulting in a spatially heterogeneous concentration gradient. At low concentrations (50–200 nM), NO facilitates angiogenesis, promotes immune evasion, enhances the function of regulatory T cells (Tregs) via the IDO1-Kyn-AhR pathway, and drives TAMs towards M2 polarization. Conversely, at high concentrations (> 500 nM), NO induces DNA nitrosative damage (e.g., 8-nitroguanine) and inhibits mitochondrial respiration in T cells, thereby diminishing their cytotoxic efficacy.HPV further contributes to T cell dysfunction by synergistically upregulating inducible nitric oxide synthase (iNOS) and arginase, leading to the depletion of arginine within the microenvironment. Emerging therapeutic strategies aimed at the nitric oxide (NO) pathway include the use of iNOS inhibitors, such as 1400 W, in combination with programmed cell death protein 1 (PD-1) antibodies, dual-targeting NOS/COX-2 inhibitors, as well as HPV-specific nanocarriers, engineered Lactobacillus, and advanced vaginal rings that enable real-time monitoring of NO concentration for precise therapeutic delivery.
Source: Discover Medicine
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $1,290
OpenAlex ID: W7225647084