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Background For over 30 years, microbial immunotherapy with Bacillus Calmette-Guérin (BCG) has been the standard-of-care for non-muscle invasive bladder cancer (NMIBC). However, global demand for BCG exceeds supply and BCG therapy is associated with high treatment burden and low patient compliance. Most novel NMIBC therapies in development either target BCG unresponsive patients or rely on combination with BCG and thus share its shortcomings. There remains a significant need for innovative therapies to replace BCG in NMIBC treatment, and live attenuated Salmonella Typhi ZH9 offers a promising alternative, both as a monotherapy and as a combination partner.Methods Efficacy of ZH9 was investigated in syngeneic mouse MB49 and p53 -/Pten - GEMM orthotopic tumor models in which animals were treated in the bladder via catheterization, with or without combination intraperitoneal anti-PD-L1 or anti-PD-1 treatment. Immune responses were characterised by flow cytometry and histology analyses of bladder tissue.Results Intravesical ZH9 monotherapy following orthotopic MB49 tumour inoculation demonstrated significant survival benefit compared to both vehicle control and BCG treatments. A single administration of ZH9 was efficacious, inducing significantly greater magnitude and duration of immune responses than standard-of-care BCG, and resulting in systemic anti-tumor immunity that protected against both local bladder and distant MB49 tumors. Combination of local ZH9 treatment with regimens of checkpoint inhibitor antibodies anti-PD-L1 (MB49 model) and anti-PD-1 (GEMM model) that were otherwise ineffective, led to significant efficacy, demonstrating true synergy of local ZH9 treatment with systemic immunotherapies.Conclusions These data support ZH9 as a superior first-line monotherapy and a potent combination partner for checkpoint inhibitors in bladder cancer, demonstrating enhanced efficacy and the potential to reduce patient treatment burden, lower healthcare costs, and overcome supply challenges through scalable manufacturing. Clinical evaluation of ZH9 in a Phase 1b study evaluating safety, pharmacology, and early efficacy in NMIBC is ongoing ( NCT06181266).Ethics Approval Animal studies were conducted under approval from Pennsylvania State College of Medicine Institutional Animal Care and Use Committee approval number 47682, or in compliance with the University of Lausanne Institutional regulations and approved by the veterinarian authorities of the Canton de Vaud (authorization VD3856).