This study assessed the safety and efficacy of OncoTherad^® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients’ mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1–2 events. OncoTherad^® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1⁺ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad^® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.

Bladder cancer (BC) stands as the second most common urinary tract malignancy. Recent years have witnessed a growing interest in investigating energy metabolism to help with better understanding the energy sources harnessed by tumor cells. The aims of the present study are to feature and compare cell energy metabolism profiles among different histological grades of non-muscle-invasive BC (NMIBC) by adjusting their bioenergetic cellular indexes based on the specific tumor types. Forty urinary bladder tissue samples from patients both with and without a diagnosis of urothelial lesions were collected. Subsequently, samples were categorized into four groups comprising ten samples each, namely: normal (no urothelial lesions) group, low-grade pTa group, high-grade pTa group, and high-grade pT1 group. These tissue samples were examined by means of immunohistochemistry and Western blotting to assess proteins involved in cell energy metabolism. Based on the current findings, the normal and low-grade pTa groups presented clear preference for the oxidative phosphorylation pathway; consequently, they recorded high bioenergetic cellular index. On the other hand, both the high-grade pTa and pT1 groups presented proclivity towards the glycolytic pathway. These observations, mainly those associated with the bioenergetic cellular index, hold promising clinical relevance in the management of BC. Given the often aggressive and potentially debilitating nature of treatments applied to this neoplasia type, the current study offers invaluable insights on this topic and emphasizes changes in the bioenergetic cellular index at different NMIBC grades, which could serve as potential markers for both the diagnosis and prognosis of NMIBC patients.