Inflammatory Bursts as Stochastic Triggers in Cancer Initiation

This opinion article proposes the “inflammatory burst” model, positing that intense, transient inflammatory escalations superimposed on chronic inflammation act as decisive stochastic triggers for cancer initiation-complementing the permissive role of somatic mutations. We define inflammatory bursts as high-amplitude, short-lived exacerbations within a chronically inflamed microenvironment, capable of overriding cellular differentiation via sustained nuclear factor kappa B (NF-κB)/signal transducer and activator of transcription 3 (STAT3) activation and dysregulated Wnt/β-catenin signaling, thereby driving an atavistic reversion to a cancer stem cell state. The dual, stage-dependent role of inflammation is illustrated through mechanisms such as Williams syndrome transcription factor (WSTF) nuclear autophagy, which amplifies bursts during initiation but is suppressed to aid immune evasion during progression. This framework shifts the clinical paradigm toward “cancer interception”—a prevention-oriented strategy aimed at selectively dampening pathological inflammatory peaks while preserving immune surveillance, thereby preventing malignant transformation in high-risk individuals.