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CTLs are mainly activated by T cell receptors (TCRs) after recognizing the peptide-bound class I major histocompatibility complex, and subsequently kill virus-infected cells and tumor cells. Therefore, identification of antigen-specific CTLs and their TCRs is a promising agent for T-cell based intervention. Currently, the experimental identification and validation of antigen-specific CTLs is well-used but extremely resource-intensive. The machine learning methods for TCR-pMHC prediction are growing interest particularly with advances in single-cell technologies. This review clarifies the key biological processes involved in TCR-pMHC binding. After comprehensively comparing the advantages and disadvantages of several state-of-the-art machine learning algorithms for TCR-pMHC prediction, we point out the discrepancies with these machine learning methods under specific disease conditions. Finally, we proposed a roadmap of TCR-pMHC prediction. This roadmap would enable more accurate TCR-pMHC binding prediction when improving data quality, encoding and embedding methods, training models, and application context. This review could facilitate the development of T-cell based vaccines and therapy.<\/jats:p>","DOI":"10.1093\/bib\/bbaf327","type":"journal-article","created":{"date-parts":[[2025,7,13]],"date-time":"2025-07-13T21:15:22Z","timestamp":1752441322000},"source":"Crossref","is-referenced-by-count":3,"title":["A roadmap for T cell receptor-peptide-bound major histocompatibility complex binding prediction by machine learning: glimpse and foresight"],"prefix":"10.1093","volume":"26","author":[{"given":"Furong","family":"Qi","sequence":"first","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiang","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yao","family":"Xuan","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingyin","family":"Cao","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunyun","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihan","family":"Ren","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province ,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3544-1389","authenticated-orcid":false,"given":"Zheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People\u2019s Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology , Shenzhen 518112, Guangdong Province 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