The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.

Victor V Pleshkan; Liya G Kondratyeva; Marina V Zinovyeva; Olga A Bezborodova; Irina V Alekseenko; Peter V Shegay; Andrey D Kaprin

doi:10.3389/fimmu.2026.1930908

PubMed · 42683335

The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.

Victor V Pleshkan·Liya G Kondratyeva·Marina V Zinovyeva·Olga A Bezborodova·Irina V Alekseenko·Peter V Shegay·Andrey D Kaprin

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Abstract

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's 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 "TRIM-Cancer Paradox" 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-Cancer Paradox as a novel design principle for next-generation rBCG platforms that transcend traditional vaccinology and cancer immunotherapy applications.

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Humans Trained Immunity BCG Vaccine Immunotherapy Neoplasms Animals Immunity, Innate Cancer Vaccines Host-Directed Therapy BCG bacillus Calmette-Guérin cancer heterologous protection immunotherapy recombinant BCG trained immunity vaccines Journal Article Review

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BibTeX RIS

Victor V Pleshkan, Liya G Kondratyeva, Marina V Zinovyeva, Olga A Bezborodova, Irina V Alekseenko, Peter V Shegay, Andrey D Kaprin. 2026-08-18. The TRIM-cancer paradox: BCG as a programmable vaccine platform and a mechanistic probe for rational immunotherapy design.. https://doi.org/10.3389/fimmu.2026.1930908

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