Clinical and translational profiling of oncotherad (MRB-CFI-1) nanoimmunotherapy identifies HER-2/SERBP1–associated recurrence and HABP4/IFN-γ–associated disease control in pT1 non-muscle-invasive bladder cancer after BCG failure

To evaluate the clinical and translational effects of OncoTherad (MRB-CFI-1) nanoimmunotherapy and to investigate biomarkers associated with therapeutic response in patients with Bacillus Calmette-Guérin (BCG)-unresponsive pT1 non-muscle invasive bladder cancer (NMIBC). A retrospective observational cohort of 21 patients with BCG-unresponsive pT1 NMIBC treated with OncoTherad was analyzed. Tumor samples obtained before and after treatment were evaluated according to clinical outcome. Immunohistochemistry was performed to quantify human epidermal growth factor receptor 2 (HER-2), SERPINE1 mRNA-binding protein 1 (SERBP1), hyaluronic acid-binding protein 4 (HABP4), and IFN- γ expression. In parallel, high-content image-based phenotypic profiling was performed in 5637 urothelial carcinoma cells to investigate treatment-associated cellular remodeling. OncoTherad achieved a pathological complete response rate of 71.4%, with a mean recurrence-free survival of 21.2 months and a low progression rate of 4.8%. HER-2 and SERBP1 expression were significantly associated with recurrence and reduced recurrence-free survival, whereas increased HABP4 and IFN- γ expression correlated with sustained disease control. Phenotypic profiling demonstrated reproducible alterations in nuclear architecture and vesicular organization, supporting coordinated cellular reprogramming associated with innate immune activation. Histopathological analyses additionally demonstrated tumor downstaging in recurrent cases, suggesting attenuation of tumor aggressiveness after therapy. Collectively, the integration of clinical outcomes, tissue biomarker profiling, and machine learning-based phenotypic analyses provides a framework supporting biomarker-oriented bladder-preserving immunotherapy in refractory NMIBC. OncoTherad demonstrated promising immunomodulatory and antitumor activity in BCG-unresponsive pT1 NMIBC. HER-2, SERBP1, HABP4, and IFN- γ emerged as candidate biomarkers associated with therapeutic response and clinical outcome, supporting further prospective validation in larger multicenter studies.