Reprogramming innate immune memory in bladder cancer: the proposed bone marrow-bladder axis and next-generation BCG-based immunotherapies

Intravesical Bacillus Calmette-Guérin (BCG) remains the standard adjuvant treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), yet the mechanisms underlying its durable clinical benefit and treatment resistance remain incompletely understood. Although BCG has traditionally been regarded as a local immunotherapy, emerging clinical and preclinical evidence suggests that intravesical BCG can induce trained-immunity-associated systemic immune changes, including alterations in circulating innate immune responses and hematopoietic programming. In this Review, we propose the bone marrow-bladder axis as a hypothesis-generating conceptual framework linking local microbial sensing with systemic hematopoietic responses that may contribute to sustained myeloid and adaptive antitumor immunity. Building upon this framework, we further introduce the Failure-to-Train (FTT) model, which proposes that selected immune-training-related mechanisms may contribute to heterogeneous patterns of BCG failure through disruption of productive immune training at distinct stages of the proposed immune-training circuit. Finally, we discuss the implications of this framework for biomarker development, experimental validation and mechanism-guided immunotherapy. By considering systemic immune training as a potential contributor to BCG responses, this Review provides a conceptual framework for investigating treatment response and resistance and for developing testable strategies for next-generation immunotherapy.