Persistent NET states link lesion-related microbial signals to the cold tumor-related local restrictive environment:...

Cold tumors often show poor effector immune cell entry or impaired effector function and therefore respond poorly to immunotherapy. Growing evidence suggests that neutrophil extracellular traps (NETs) are not simply by-products of tumor-associated inflammation. In some tumor settings, they can persist within lesions and act as retained local mediators. Among the upstream factors that may sustain this process, microbial signals warrant particular attention. In selected cancers, persistent lesion-related microbial signals may convert an initially transient NET response into persistent NET states. These states are linked to restricted effector immunity, stromal remodeling, vascular abnormalities, and other tumor-promoting consequences. This review reorganizes current evidence around the axis of lesion-related microbial signals, persistent NET states, and the cold tumor-related local restrictive environment. On this basis, a context-dependent working model is proposed in which lesion-related microbial signals contribute to the formation and maintenance of this environment through persistent NET states. Support for this sequence is not uniform across tumor types. Colorectal cancer currently provides the clearest line of support. Hepatocellular carcinoma is better understood as a setting in which the same framework is expressed more through organ conditioning and local amplification. Evidence from other tumors remains more limited and is often partial rather than fully resolved. Most available studies are still preclinical. Even so, current findings suggest that reducing sustained microbial stimulation or directly intervening in persistent NET states may help relieve this restrictive environment and inform future translational strategies.