Premalignant immune remodeling in laryngeal carcinogenesis: a framework to define when immune interception becomes testable

Laryngeal dysplasia presents a clinical dilemma because lesions with similar histology can have different outcomes. Single-cell, spatial and pathology studies show immune remodeling before invasion, yet differences between lesion stages do not establish future progression risk within dysplasia. We consider three potentially coexisting explanations of a premalignant immune signal, namely reactive recruitment, ineffective antitumor activity and a stromal niche that supports progression. Each requires different spatial and functional evidence. We adapt established validation principles to five evidence requirements concerning lesion identity, future invasion, spatial and functional state, causal reversibility and clinical readiness. Their purpose is to separate risk stratification from target validation, rather than require one marker to perform both roles. Existing laryngeal studies address parts of this framework, but none establishes that targeting a premalignant immune circuit prevents cancer. The immediate priority is to compare histologically comparable lesions with known outcomes and test candidate interactions in models that retain noninvasive epithelium. Short window studies may subsequently establish target engagement and biological activity, but clinical prevention requires separate evidence of reduced invasive cancer risk and acceptable harm.