From Early Activity to Phase III Program Attrition: The Anti-TIGIT Translation Gap

T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) has a compelling biological rationale as a partner for programmed cell death protein 1 or programmed death-ligand 1 blockade. Early clinical activity supported development in lung, hepatocellular, and gastroesophageal cancers, but randomized studies have not established broadly reproducible incremental benefit over contemporary immunotherapy backbones. This Perspective distinguishes observed clinical outcomes from explanations inferred from experimental or exploratory translational studies. Small early trials, subgroup selection, nonidentical controls, endpoint maturity, and multiplicity complicate interpretation; failure of a prespecified endpoint does not prove biological inactivity. CD226 dysfunction, immune-cell state, Fc-dependent effects, backbone redundancy, and adaptive resistance remain candidate explanations rather than demonstrated causes of phase III failure. SKYSCRAPER-08 establishes efficacy of a TIGIT-containing regimen without isolating its TIGIT component, whereas subsequent SKYSCRAPER-07 comparisons are descriptive after failure of hierarchical testing. The belrestotug program further illustrates why improved response alone is insufficient for advancement. We propose prospectively specified clinical precision requirements, mechanism-linked intratumoral pharmacodynamic activity, and practical biomarker validation before confirmatory expansion. These development criteria are proposals requiring prospective evaluation, not established selection rules.