Abundance is not survival: Intratumoural immune-cell fate as a missing endpoint in antibody-drug conjugate and checkpoint blockade combinations for triple-negative breast cancer

Antibody-drug conjugates (ADCs) have reshaped metastatic triple-negative breast cancer, and combining them with checkpoint inhibitors is close to consensus: cytotoxic payloads kill tumour cells in ways that release antigen and expose damage-associated signals. We argue that a specific endpoint is missing from both sides of the question. Preclinical ADC studies report the abundance and activation phenotype of intratumoural immune populations, not their survival, and that reflects endpoint convention, not technical limitation. Payload diffusion is governed by the physical chemistry of the released molecule and the geometry of the tissue it crosses, not by the identity of the cell it reaches; the dendritic cells and lymphocytes on which checkpoint blockade depends occupy the same space. Only three randomised breast cancer datasets permit interpretation, none is powered to isolate the checkpoint contribution, and predictive biomarkers have not performed. We examine payload distribution in tissue, immune-population exposure and susceptibility, the consequences of payload class, and the lymphodepletion, corticosteroid and growth-factor exposures that trial protocols impose. Evidence is graded as direct, indirect, inferred or not measured, and it runs both ways: antigen-independent uptake is documented, yet microtubule payloads mature intratumoural dendritic cells and auristatin conjugates against 4-1BB failed to deplete activated T cells at any drug-to-antibody ratio tested. Intratumoural immune-cell fate is therefore an unmeasured variable rather than a demonstrated cause, and three propositions treated as settled mechanism should be restated as hypotheses. Resolving them requires matched-linker conjugates, spatially resolved survival endpoints, and covariates that trials can analyse retrospectively.