The dual legacy of BCG: a century of tuberculosis prevention and the evolving pursuit of trained immunity-based therapies.

The Bacillus Calmette-Guérin (BCG) vaccine, a live-attenuated derivative of Mycobacterium bovis, has long been central to global tuberculosis prevention. Although it protects well against severe childhood TB, its efficacy against adult pulmonary TB is variable. At the same time, epidemiological and clinical observations suggest that BCG may reduce all-cause mortality and protect against infections beyond TB. Randomised trials have reported lower neonatal all-cause mortality and fewer sepsis-related deaths, supporting the idea of broader immunological benefits. These heterologous effects are proposed to be derived from trained immunity, a form of functional reprogramming of innate immune cells driven by epigenetic and metabolic changes. In some settings, BCG may also induce trained tolerance, leading to a more suppressive immune state, based mainly on animal and in vitro evidence. Clinically, intravesical BCG is an established local immunotherapy for non-muscle-invasive bladder cancer, with current evidence and emerging data suggesting that its effects may extend beyond the bladder through systemic immune training. However, repurposing BCG for other cancers, non-oncological autoimmune diseases, and respiratory tract infections remains established in experimental animal models but is represented with mixed efficacy accompanied by inconclusiveness in human trials and mostly in preclinical or early-phase evidence. Major barriers to translation include strain variability, lack of standardised dosing, uncertain durability, and unresolved long-term safety concerns. Future progress will depend on engineered BCG derivatives, improved delivery systems, rational combination therapies, and well-designed controlled clinical trials.Methodology: Literature was identified through searches of PubMed, Google Scholar, and the Cochrane Library, from database inception to 2026, with a primary focus on studies published between 2011 and 2026.