Decoding Immune Mechanisms in BCG-unresponsive Non-muscle Invasive Bladder Cancer

Non-muscle-invasive bladder cancer (NMIBC) accounts for roughly 75% of all bladder cancer cases. For patients with intermediate- and high-risk disease, intravesical Bacillus Calmette-Guérin (BCG) remains the standard treatment, yet it fails in up to 40% of cases. While radical cystectomy is the most effective salvage option, it carries significant morbidity and long-term quality-of-life consequences, highlighting the urgent need for bladder-sparing alternatives. Advancing such therapies requires a deep understanding of the immunologic mechanisms within the tumor microenvironment (TME). This review offers a concise overview of the immunologic mechanisms underlying BCG therapy, along with a detailed examination of the multifactorial immune evasion mechanisms that contribute to its failure in NMIBC. Within the TME, ten principal mechanisms of immune suppression have been identified. These include the activity of myeloid-derived suppressor cells, tumor-associated macrophages, regulatory T cells, and tolerogenic dendritic cells, as well as signaling pathways such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1), the natural killer group 2A/human leukocyte antigen-E (NKG2A/HLA-E) checkpoint, and the release of immunomodulatory molecules within the TME. Further contributors to immune evasion include cluster of differentiation 6/activated leukocyte cell adhesion molecule (CD6-ALCAM) signaling, effector T cell exhaustion, and cancer-associated fibroblasts. Collectively, these mechanisms disrupt antigen presentation, suppress cytotoxic immune responses, and facilitate tumor progression, ultimately undermining the efficacy of BCG therapy. In parallel, we highlight emerging intravesical immunotherapies for BCG-unresponsive NMIBC with carcinoma in situ, including nadofaragene firadenovec (Adstiladrin), nogapendekin alfa inbakicept-pmln (Anktiva), cretostimogene grenadenorepvec (CG0070), and detalimogene voraplasmid (EG-70). These agents employ diverse platforms, including gene therapy, cytokine stimulation, oncolytic virotherapy, and plasmid-based immune activation, to enhance antitumor responses. While early and late-phase clinical trials have shown promising response rates and favorable safety profiles for these novel agents, direct comparisons remain limited due to the reliance on single-arm study designs. The lack of comparative data, coupled with the absence of predictive biomarkers of response, complicates treatment selection. Our review underscores that developing effective therapies for BCG-unresponsive disease will require combination strategies targeting multiple immune escape mechanisms that shape immune dynamics within the TME.