B cells play a diverse role in the tumor microenvironment (TME) of solid tumors, influencing immune responses, tumor progression, and therapeutic outcomes. Depending on their activation state and interactions with other tumor components, they can exert both pro- and anti-tumor functions. They can promote tumor growth by secreting immunosuppressive cytokines or boost antitumor immunity by producing antitumor antibodies, presenting antigens, and activating T cells. Studying the effect of the TME on the phenotype and functionality of B cells is of great importance as their interactions with other TME components, such as cancer cells and stromal cells shape the immune landscape of the tumor. Gaining insight into these interactions sheds light on the mechanisms used by the tumor to evade immune detection. In this chapter, I summarize our current 3D co-culture system designed to investigate the effects of the TME on the functionality of B lymphocytes, using pancreatic ductal adenocarcinoma as a solid tumor model.