{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:33:23Z","timestamp":1787067203512,"version":"build-2736575974"},"reference-count":156,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013400","name":"National Research Center \"Kurchatov Institute\"","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013400","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>BCG, a first-generation live vaccine, is being reconsidered as an immunological platform. Interest in its heterologous protection intensified during the pandemic. However, large-scale clinical trials revealed inconsistencies in the efficacy of native BCG. This review argues that BCG\u2019s main value lies in its potential as a modifiable vector platform and in its ability to reveal tractable molecular pathways for therapeutic design. This review summarizes the molecular basis of BCG-induced trained immunity (TRIM), focusing on PRR-driven signaling, metabolic rewiring, and epigenetic remodeling in innate immune cells and hematopoietic progenitors. It also maps their convergence with pathways that sustain pro-tumorigenic inflammation. The original conceptual paradigm of the \u201cTRIM-Cancer Paradox\u201d is presented. This paradigm posits that the same innate immune circuits that mediate protective heterologous responses can drive tumor-promoting inflammation and immune escape under conditions of chronic dysregulation. Recombinant BCG (rBCG) is further analyzed as a strategy to rationally amplify or redirect these circuits, the current clinical landscape of BCG-based interventions across various diseases and oncological malignancies is highlighted, and specific molecular nodes that could be exploited to increase the precision, efficacy, and safety of rBCG-based therapies are identified. Overall, this review proposes BCG a programmable immunological platform and to use the TRIM\u2013Cancer Paradox as a novel design principle for next-generation rBCG platforms that transcend traditional vaccinology and cancer immunotherapy applications.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1930908","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:57:31Z","timestamp":1787065051000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design"],"prefix":"10.3389","volume":"17","author":[{"given":"Victor V.","family":"Pleshkan","sequence":"first","affiliation":[{"name":"Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"KC NBICS-Nature-Like Technologies, NRC \u201cKurchatov Institute\u201d","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya G.","family":"Kondratyeva","sequence":"additional","affiliation":[{"name":"Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"KC NBICS-Nature-Like Technologies, NRC \u201cKurchatov Institute\u201d","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina V.","family":"Zinovyeva","sequence":"additional","affiliation":[{"name":"Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga A.","family":"Bezborodova","sequence":"additional","affiliation":[{"name":"Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences","place":["Moscow, Russia"]},{"name":"Department of Pharmacology of Biomedical Products, P. Hertsen Moscow Oncology Research Institute, National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina V.","family":"Alekseenko","sequence":"additional","affiliation":[{"name":"Department of Genomics and Postgenomic Technologies, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences","place":["Moscow, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter V.","family":"Shegay","sequence":"additional","affiliation":[{"name":"Department of Pharmacology of Biomedical Products, P. 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