From ICI Resistance to Therapeutic Vulnerability: A Resistance-State Framework for Appraising Antibody-Drug Conjugate...

Antibody-drug conjugates (ADCs) can alter tumor-immune interactions, but activity in immune checkpoint inhibitor (ICI)-resistant disease, ADC-ICI combination benefit, functional checkpoint re-enablement, and causal resensitization are often conflated. We propose a resistance-state appraisal framework that distinguishes three outcomes. Re-enable denotes renewed therapeutic contribution from a previously ineffective checkpoint pathway in an ADC-containing context. Bypass denotes ADC activity in an ICI-resistant state without demonstrated restoration of that pathway. Prime denotes immune remodeling that lowers the threshold for checkpoint responsiveness when prior ICI resistance has not been established. We organize potentially actionable biology around immunogenic visibility and antigen presentation, T-cell competence, stromal access, suppressive cellular or metabolic states, effector trafficking, and adaptive checkpoint dependency. Current evidence supports functional re-enablement in selected preclinical models and provides clinical signals compatible with, but not establishing, functional re-enablement after documented PD-1/PD-L1 failure; causal, temporally separable restoration of intrinsic ICI sensitivity remains rarely demonstrated. We therefore propose an evidentiary hierarchy that progresses from concurrent combination activity to controlled incremental checkpoint contribution and, when feasible, temporally separated state-conversion and rechallenge designs. Interpretation is constrained by lesion-level heterogeneity, imperfect preclinical modeling and ADC pharmacokinetics, and the practical or ethical infeasibility of fully separated rechallenge designs. Secondary hypotheses concerning residual immune competence and dose-time alignment are treated as research constructs rather than validated biomarkers or dosing rules. The framework is intended to make resensitization claims auditable and to guide experiments and clinical trials that distinguish therapeutic activity from genuine restoration of checkpoint vulnerability.