Functional Vascularization in Tumor Organoid and Tumor-on-Chip Models: Evidence Requirements for Attributing Therapy-Resistance Mechanisms

Vascularized tumor organoid and tumor-on-chip models are increasingly used to examine treatment response, yet a weak therapeutic effect does not by itself identify the failed transport or biological step. Reduced efficacy may result from inadequate delivery, altered endothelial transport or signaling, stromal protection, impaired immune access or function, tumor-intrinsic resistance, or several processes acting together. A structured literature search and narrative synthesis were combined with a focused qualitative appraisal of 25 eligible primary studies to determine what evidence is needed to distinguish these explanations. Twenty-one studies included a relevant comparator, a mechanism-directed perturbation, and a functional readout; four directly tested a principal competing explanation, and three included rescue or reversal. Most studies therefore supported a contributory mechanism under the tested conditions rather than an exclusive causal attribution, leaving transport, stromal, immune, and tumor-intrinsic routes incompletely separated. The synthesis defines five candidate failed-step classes and specifies the comparisons, local-exposure or step-resolved measurements, perturbations, orthogonal readouts, and alternative tests needed for each. Mechanistic attribution is most secure when the proposed bottleneck is measured directly, manipulated experimentally, and distinguished from credible alternatives. Clinical application will additionally require context-of-use-specific evidence of analytical reproducibility, reference treatments, prespecified acceptance criteria, and association with clinically relevant outcomes.