{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T13:48:32Z","timestamp":1782308912773,"version":"3.54.5"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T00:00:00Z","timestamp":1780531200000},"content-version":"vor","delay-in-days":3,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62272300"],"award-info":[{"award-number":["62272300"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>T cell receptor (TCR) recognition of peptide-major histocompatibility complex (pMHC) complexes is central to adaptive immunity, yet rational design of immunogenic epitopes remains elusive due to complex triplet binding constraints and data scarcity. No existing method can generate epitopes satisfying simultaneous requirements for antigenicity, MHC presentation, and TCR specificity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We present EPIC, a multi-objective diffusion framework that decomposes TCR-pMHC binding into three biologically grounded sub-tasks, enabling training-free gradient guidance without end-to-end retraining. By integrating ESM-based classifiers with a peptide diffusion generator, EPIC leverages heterogeneous immunological interaction datasets to generate diverse, context-aware epitopes. EPIC-designed top-three epitopes achieve lower predicted interface energies compared to ground-truth epitopes in 78.31% of test cases, while maintaining 80.1% sequence novelty and comparable structural confidence. Generated epitopes exhibit 100% uniqueness, high diversity (64.05%), and high antigenicity scores (0.4723). To our knowledge, EPIC is the first computational framework capable of de novo epitope design while explicitly integrating the triplet constraints of TCR-pMHC binding. This paradigm shift from discovery to design unlocks new potential for personalized cancer vaccines, precision adoptive T cell therapy, and rapid response to emerging infectious diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>The source code of EPIC is available at https:\/\/github.com\/Octopus125\/EPIC and archived on Zenodo (DOI: 10.5281\/zenodo.18537646).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btag358","type":"journal-article","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T11:46:41Z","timestamp":1780487201000},"source":"Crossref","is-referenced-by-count":0,"title":["EPIC: multi-objective guided diffusion for epitope design in TCR-pMHC complexes"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3688-0970","authenticated-orcid":false,"given":"Yueshan","family":"Huang","sequence":"first","affiliation":[{"name":"AGI Institute, School of Computer Science, Shanghai Jiao Tong University , Shanghai 200240,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0628-8714","authenticated-orcid":false,"given":"Gufeng","family":"Yu","sequence":"additional","affiliation":[{"name":"AGI Institute, School of Computer Science, Shanghai Jiao Tong University , Shanghai 200240,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letian","family":"Chen","sequence":"additional","affiliation":[{"name":"AGI Institute, School of Computer Science, Shanghai Jiao Tong University , Shanghai 200240,","place":["China"]},{"name":"Shanghai Innovation Institute , Shanghai 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