Dual Role of Nitric Oxide in Tumor Immunity and Its Therapeutic Application

Nitric oxide (NO) is a key bioactive signaling molecule produced primarily by L-arginine by inducible NO synthase (iNOS), which is involved in signal transduction and performs a variety of biological functions. As the mainstay of the immune response, macrophage polarization is a dynamic and reversible process, allowing them to shift their functional states and immune-inflammatory properties in response to changing environmental cues. M1-type macrophages are polarized by stimuli such as lipopolysaccharide or interferon gamma. These pro-inflammatory cells secrete tumor necrosis factor alpha, interleukin-1β (IL-1β), IL-6, and other pro-inflammatory factors, which serve to initiate and amplify the inflammatory response. By contrast, M2-type macrophages are induced by IL-4 or IL-13 and express high levels of anti-inflammatory mediators such as IL-10 and transforming growth factor beta, which inhibit inflammation and promote tissue repair. Macrophages in the tumor immune microenvironment produce NO via arginine metabolism, with important impacts on tumorigenesis and immune escape. In turn, NO production regulates macrophage function by inducing a shift from the M2 type (which promotes tumor growth) to the M1 type (which suppresses tumor growth). In addition, NO affects the tumor immune response by regulating T-cell activity. Relevant therapeutic strategies for targeting NO include arginase (ARG) inhibitors, NO donors, and iNOS overexpression. This review summarizes the complex role of NO in tumor immunity and related therapeutic strategies. While the findings provide new directions for cancer immunotherapy, further research is needed to fully understand specific mechanisms, such as the dynamic regulation of the NO concentration threshold, the clinical translation of these findings, and the seemingly contradictory role of NO in immune cell function, ultimately leading to more effective treatment options.