Acute respiratory viral inflammation and metastatic dormancy: direct evidence, mechanistic convergence, and research priorities.

Metastatic relapse can arise years after apparently successful treatment because disseminated cancer cells (DCCs) persist in reversible states of cellular, angiogenic, or immune-mediated dormancy. The strongest direct evidence that acute viral inflammation can disturb this equilibrium currently comes from experimental breast-cancer lung-dormancy models in which influenza A virus or SARS-CoV-2 promoted DCC cell-cycle re-entry and metastatic expansion, with interleukin-6 (IL-6) required for the initial awakening phenotype. Human findings reported in the same study are observational and do not establish that respiratory viral infection causes metastatic relapse. This hypothesis-generating Perspective therefore separates direct viral-dormancy evidence from direct inflammation-dormancy evidence, established metastatic-niche biology, mechanistic extrapolation, and unvalidated clinical hypotheses. We critically evaluate IL-6/JAK/STAT3 signaling, the time-dependent balance between antiviral and antitumor immunity, neutrophil extracellular trap-mediated matrix remodeling, epithelial RNA sensing, endothelial and perivascular responses, and selected extracellular-vesicle mechanisms. The evidence does not establish a universal infection-to-niche-to-relapse pathway across cancers or organs. Instead, it supports a context-dependent model in which respiratory infection may transiently perturb the DCC-niche equilibrium in susceptible settings. Priority studies should independently replicate the pulmonary phenotype, define causal timing, distinguish local lung injury from systemic effects, test cross-cancer and cross-organ generalizability, and prospectively evaluate human associations. No post-viral biomarker panel, intensified imaging strategy, or pathway-directed intervention is currently validated for routine clinical use.