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Although single-cell RNA sequencing enables characterization of heterogeneous resistance-associated states, single-cell drug-response phenotype prediction remains challenging because of sparsity, noise, class imbalance, and limited mechanistic interpretability. Here, we present scRADAR (Response Analysis via Drug-Aware Routing), a mechanism-guided prototype routing framework for predicting and interpreting drug-response phenotypes at single-cell resolution. Rather than relying on cell-line\u2013anchored transfer learning, scRADAR learns directly from labeled single-cell cohorts. The framework integrates metabolic and signaling pathway activities to form a dual-view cellular representation, conditions pathway embeddings on drug mechanisms through feature-wise linear modulation, and uses sparse prototype routing to decompose predictions into interpretable response archetypes. Across nine independent cohorts, scRADAR showed strong predictive performance and consistent cross-cohort behavior, particularly under imbalanced settings. Post hoc attribution analyses highlighted candidate TGF-\u03b2-associated epithelial-to-mesenchymal transition signatures in Erlotinib-associated Resistant-labeled states and cytoskeletal\/metabolic response-associated signatures in BET-inhibitor-associated Resistant-labeled states. These results suggest that scRADAR provides an interpretable framework for single-cell drug-response phenotype prediction and for generating hypotheses about resistance-associated programs from heterogeneous tumor transcriptomes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1014392","type":"journal-article","created":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:52:19Z","timestamp":1782496339000},"page":"e1014392","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["scRADAR: Dissecting intratumoral drug response heterogeneity at single-cell resolution via mechanism-guided prototype routing"],"prefix":"10.1371","volume":"22","author":[{"given":"Ren","family":"Qi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Teng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey 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