The biological basis of BCG immunotherapy is complex. When the bacterium is introduced into the bladder, it attaches to fibronectin and other extracellular matrix proteins on the surface of urothelial cells, where it is internalized by both tumor cells and antigen-presenting cells. This internalization sets off a cascade of innate immune signaling, including the activation of toll-like receptors and the release of pro-inflammatory cytokines such as interleukin-1, interleukin-6, interleukin-8, and tumor necrosis factor alpha. Over the following weeks, this acute inflammatory response evolves into an adaptive immune reaction characterized by the infiltration of CD4 and CD8 T lymphocytes, natural killer cells, and granulocytes, which together work to eliminate residual tumor cells and prevent recurrence.

However, bladder tumors are not passive targets. Over time, many lesions develop sophisticated mechanisms of immune evasion that allow them to survive despite an active local immune attack. One of the most important of these mechanisms involves the upregulation of immune checkpoint molecules, particularly programmed death-ligand 1, or PD-L1, on the surface of tumor cells. When PD-L1 engages its receptor, PD-1, on infiltrating T cells, it delivers an inhibitory signal that effectively disarms the cytotoxic response. Research has shown that PD-L1 expression in bladder tumors can increase after BCG treatment, suggesting that the very inflammation triggered by the therapy may inadvertently select for tumor clones that exploit checkpoint pathways to escape destruction.

Beyond checkpoint upregulation, tumors employ a range of additional strategies to resist immune attack. Some bladder cancers secrete immunosuppressive cytokines such as interleukin-10 and transforming growth factor beta, which dampen T cell activation and promote the recruitment of regulatory T cells. Others remodel their tumor microenvironment by increasing the density of myeloid-derived suppressor cells and tumor-associated macrophages that skew the local immune landscape away from an antitumor phenotype. Genetic alterations in tumor suppressor pathways and antigen presentation machinery can further impair the ability of the immune system to recognize malignant cells, creating a multidimensional wall of resistance that single-agent therapies struggle to penetrate.

This growing appreciation of tumor immune evasion has reshaped the therapeutic landscape. Rather than relying on BCG alone, investigators are now exploring rational combination strategies that pair BCG with agents designed to block specific escape pathways. Immune checkpoint inhibitors, particularly antibodies targeting PD-1 and PD-L1, have emerged as leading candidates for such combinations. By releasing the brakes on T cells that BCG has already activated, checkpoint blockade may restore the cytotoxic function that tumors have suppressed, creating a synergistic effect in which one agent primes the immune system and the other unleashes it.

Clinical trials are actively testing this hypothesis. Studies combining BCG with pembrolizumab, an anti-PD-1 antibody, have shown encouraging response rates in patients whose tumors did not respond to BCG alone. Other trials are evaluating combinations of BCG with interleukin-15 superagonists, which stimulate the proliferation and activation of natural killer cells and memory-like CD8 T cells, adding another layer of antitumor immunity. Gene therapy approaches, including adenoviral vectors engineered to deliver interferon alpha directly to bladder tumor cells, are also being investigated in combination with BCG and checkpoint inhibitors, aiming to enhance antigen presentation and further sensitize tumors to immune attack.

Not all combination strategies involve immunotherapy. Intravesical chemotherapy agents such as gemcitabine and docetaxel, delivered directly into the bladder to minimize systemic toxicity, are being paired with BCG and with checkpoint inhibitors in sequential and concurrent regimens. These chemotherapy agents do more than kill tumor cells directly; emerging evidence suggests they can induce immunogenic cell death, a form of tumor cell demise that releases tumor antigens and danger signals, thereby enhancing the ability of antigen-presenting cells to stimulate an antitumor T cell response. In this way, chemotherapy may act as a catalyst that amplifies the effects of immunotherapy rather than simply an additive cytotoxic agent.

The challenges ahead are considerable. Combination therapies inevitably raise questions about toxicity, as activating multiple arms of the immune system simultaneously can increase the risk of adverse effects ranging from local bladder irritation to systemic autoimmune reactions. Patient selection is another critical variable, since not all tumors respond equally to immune-based strategies, and biomarkers capable of predicting which patients will benefit from specific combinations remain an area of intense investigation. Cost and accessibility also factor into the equation, as novel immunotherapeutic agents and gene therapies can be expensive to produce and administer.

Despite these obstacles, the momentum behind combination therapy for BCG-unresponsive bladder cancer is undeniable. The convergence of deeper mechanistic insight into tumor immune evasion, the availability of agents capable of targeting specific resistance pathways, and a robust pipeline of clinical trials testing rational combinations has created a genuine inflection point in the field. For patients whose tumors once faced limited options after BCG failure, the emerging arsenal of combination strategies offers renewed hope for durable disease control and, ultimately, improved survival without the need for radical surgery.

Subject of Research: Cancer immunology and immunotherapy resistance in bladder cancer

Article Title: Combination therapy for BCG-unresponsive non-muscle-invasive bladder cancer: biological rationale and ongoing clinical strategies

Article References: Daneshmand, S., Boorjian, S. A., Meeks, J. J., Lotan, Y., Kassouf, W., Kulkarni, G. S., Gontero, P., Albers, P., Jakobsen, J. S., & Juul, K. (2026). Combination therapy for BCG-unresponsive non-muscle-invasive bladder cancer: biological rationale and ongoing clinical strategies. Nature Reviews Urology. https://doi.org/10.1038/s41585-026-01193-0

Image Credits: AI Generated

DOI: 10.1038/s41585-026-01193-0

Keywords: bladder cancer, BCG immunotherapy, immune evasion, immunotherapy resistance, cancer immunology, combination therapy, tumor microenvironment, immune checkpoint inhibitors, oncology, clinical research, Combination, therapy