Intravesical immunotherapy with BCG (Bacillus Calmette-Guérin) is the gold-standard treatment for non-muscle-invasive bladder cancer at high risk of recurrence or progression. Despite more than 30 years of clinical experience with intravesical BCG for bladder cancer, its mechanism of antitumor effect remains unknown and no markers exist to predict response. BCG attachment to tumor cells, leading to internalization and processing of the mycobacterium, likely plays a crucial role in activation of BCG-mediated antitumor activity It has been shown that macropinocytosis is the mechanism by which bladder cancer cells internalize BCG. Intriguingly, the ability of bladder cancer cells to internalize BCG through macropinocytosis is dependent on the presence of certain oncogenic aberrations Particularly, it has been demonstrated that the efficacy of BCG therapy of bladder cancer might depend on uptake of BCG by bladder cancer cells due to the presence of oncogenic aberrations in the RAS, PTEN¿PI3K and Wnt/¿-catenin pathways, which lead to activation of macropinocytosis. Prospective genetic profiling of TURB specimens for mutations affecting these signaling pathways may allow clinicians to restrict BCG therapy to those patients most likely to respond. Studies have not yet evaluated the role of internalization of BCG by bladder cancer cells in vivo. Although previously published works provide an attractive model for the role of internalization by tying BCG uptake to the presence of certain oncogenic mutations, it is not known if BCG internalization by bladder cancer cells is a prerequisite for achievement of its therapeutic effect. On the basis of these premises, we here aim to evaluate whether the presence of RAS, PTEN and Wnt/¿-catenin aberrations in tumor samples from transurethral resection of the bladder (TURB) may represent predictive biomarkers of BCG efficacy in non-muscle invasive bladder cancer (NMIBC) patients.