BCG in the fight against cancer: exploring its applications in diverse tumour types and future directions

Bacillus Calmette–Guérin (BCG) was repurposed as intravesical immunotherapy for bladder cancer following its success as a tuberculosis vaccine. Its anti-tumour activity is multifaceted. Directly, BCG induces apoptosis, necrosis and oxidative stress through caspase activation, tumour necrosis factor–alpha (TNF-α) signaling and production of nitric oxide and reactive oxygen species (ROS), damaging tumour DNA and proteins [1]. BCG’s preferential cytotoxicity for tumour over normal urothelium appears to reflect selective uptake: malignant urothelial cells commonly activate Rac1/Cdc42-Pak1-dependent macropinocytosis, enabling BCG entry and concentrating downstream cytotoxic and immune effects in tumour cells [2].

BCG also acts as a pathogen-associated molecular pattern that engages pattern-recognition receptors (notably TLRs) on antigen-presenting cells (APC) and, in some contexts, on tumour cells, driving T helper 1 (Th1)-polarised cytokines (e.g., Interleukin (IL) IL-2/IL-12,‑2/IL‑12, Interferon (IFN) IFN-γ ‑γ and TNF‑α) and recruitment of CD8⁺ T cells, macrophages, natural killer cells and neutrophils. Neutrophils can contribute direct cytotoxicity via TNF-related apoptosis-inducing ligand release and neutrophil extracellular trap formation. Response heterogeneity likely reflects at least three non-mutually exclusive factors: (i) some cancer cells internalise BCG and acquire APC-like cytokine signaling; (ii) BCG can trigger caspase-dependent cytotoxicity with ROS-mediated injury and cell-cycle arrest and (iii) BCG may upregulate PD‑L1 on tumour and inflammatory cells, partially counteracting cell-mediated immunity [3].

BCG’s modern oncologic use was established in bladder cancer, where randomised trials showed intravesical BCG reduced recurrence relative to chemotherapy controls and long-term outcomes improved when induction was followed by maintenance dosing [4, 5]. International guidelines consistently recommend intravesical BCG for appropriately selected intermediate and high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumour, because it reduces recurrence and (in higher-risk groups) delays or reduces progression. For optimal efficacy, guidelines specify that BCG should not be delivered as induction alone: a complete schedule includes a 6-week induction course followed by maintenance instillations (commonly 3-weekly cycles at 3, 6, 12, 18, 24, 30 and 36 months), with duration tailored to risk, toxicity and BCG availability [6, 7]. Taken together, the randomised-trial evidence and guideline-endorsed use of intravesical BCG in NMIBC provide a clinical proof of principle that BCG can act as an effective, controllable, locally delivered immune therapy. This success has prompted efforts to redeploy BCG as an in situ immune stimulus in other tumour types.

Importantly, BCG is not a single product but a family of live-attenuated sub-strains with measurable biological and clinical differences. Comparative analyses in NMIBC suggest that strain selection can influence immunogenicity and tolerability, although adequate maintenance remains a dominant driver of durable benefit [8, 9]. These same properties matter when BCG is repurposed as a Th1-biased adjuvant in therapeutic cancer vaccines: more reactogenic preparations can amplify local innate activation and dendritic-cell recruitment, whereas less reactogenic strains may reduce injection-site morbidity and discontinuation risk [10, 11].

Interest in BCG beyond the bladder has resurfaced alongside modern immuno-oncology because BCG can (i) directly injure tumour cells, (ii) activate innate sensors that set up Th1-polarised inflammation and (iii) induce trained immunity that may heighten subsequent antitumour responses. Most contemporary programs still center on bladder cancer, but smaller bodies of evidence exist in melanoma, hepatocellular carcinoma (HCC) and vaccine-adjuvant settings.