B-cell derived chronic lymphocytic leukemia (CLL) represents the most prevalent leukemia in the western world and is characterized by the clonal expansion of leukemic B-lymphocytes. Although CLL cells experience a great longevity in vivo, they undergo spontaneous apoptosis in vitro, suggesting their dependency on supporting cell contact and factors provided by the microenvironment. In fact, bone marrow stromal cells exert a protective effect on CLL cells, prolonging their survival in vitro and contributing to drug resistance. Numerous studies investigated the underlying effects of stromal cells on CLL cells, revealing several aspects by which the bone marrow stroma affects pathogenesis and progression of the disease. However, the possibility that CLL cells assist their own protective niche has rarely been studied so far. Thus, in the course of this work we focused on the mechanisms by which stromal cells become capable of fulfilling their protective functions. Since alterations of cellular metabolism are a hallmark of cancer and frequently observed in the tumor microenvironment, we addressed the metabolic phenotype of CLL cell-experienced stromal cells. CLL cell contact led to an overall increased glycolytic activity of stromal cells as exemplified by enhanced glucose uptake accompanied by increased mRNA levels of key-glycolytic proteins. Furthermore, stromal cells were less sensitive to oxidative stress upon contact with CLL cells. This was mediated by a strengthened antioxidative capacity provided by increased levels of non-enzymatic and enzymatic antioxidants and paralleled by an increased mitochondrial fitness in CLL experienced stromal cells. Evading immune surveillance and compromising anti-cancer immune response is another important characteristic of cancers and frequently accomplished by the dysregulation of immune checkpoint molecules, whose physiological function is to provide and maintain self-tolerance. Indeed, CLL cell contact mediated the upregulation of the two prototypical immune checkpoint molecules PD-L1 and IDO in stromal cells. Our data strongly support the hypothesis, that a bi-directional communication between stromal and CLL cells exist and that CLL cells modulate their stromal niche for their own benefit.