B-cell non-Hodgkin lymphomas (B-NHLs) are a heterogeneous group of tumors deriving from the malignant transformation of B cells. The two most common B-NHL subtypes are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), which account together for 50-60% of B-NHL cases. The standard of care for advanced or transformed FL and DLBCL is a combination of chemotherapy and the anti-CD20 antibody rituximab (R-CHOP); however, this approach is curative just in a fraction of cases. In addition, despite a good characterization of the genomic lesions present in those tumors, the available targeted therapies are limited and related to only partial responses. Thus, effective and curative treatments for B-NHLs are still missing, imposing the need for the design of new therapeutic strategies for these patients. In this thesis, I characterized the mechanisms of intrinsic and acquired resistance to targeted therapies in B-NHLs and identified novel therapeutic approaches for FL and DLBCL treatment. In the first part of this thesis, I focused on the inhibition of the B cell receptor (BCR) signaling pathway in DLBCL. The propagation of the BCR signal can be blocked using the targeted BTK inhibitor ibrutinib; however, this approach is effective only in a subgroup of DLBCL patients. In my studies, I showed that, in cells intrinsically resistant to ibrutinib, the loss of BTK is compensated by an increased dependency on the PI3K/AKT pathway downstream the BCR. In addition, I proposed to target the SRC kinases which propagate the BCR signal to both BTK and PI3K/AKT, using the new inhibitor masitinib. In cell lines and patients-derived primary samples, I showed that masitinib treatment is effective in both ibrutinib-sensitive and resistant tumors, thus suggesting it as novel therapeutic approach for a broader group of patients. In the second part of this thesis, I characterized the influence of ibrutinib and masitinib treatments on tumor heterogeneity and evolution using single-cells transcriptomics approaches. I showed that, upon long-term targeted treatments, initially sensitive tumors relapse and this is associated with changes in gene expression at the single-cell level. I then identified a set of genes that might contribute to acquired resistance to these drugs. This study will serve as starting point for a broader characterization of the effect of targeted therapies on clonal dynamics and tumor heterogeneity and for the rational design of combinatorial strategies. The last part of this thesis is focused on the characterization of cathepsin S as novel therapeutic target in FL. I showed that, in FL patients, cathepsin S over-activation by a gain-of-function mutation or by gene over-expression promotes lymphomagenesis. I found that cathepsin S has an essential role in regulating the interactions of lymphoma cells with T cells infiltrated in the tumor. Indeed, deletion of cathepsin S leads to a diversification in the repertoire of antigens presented on MHC molecules, which increases tumor immunogenicity. In pre-clinical studies, I showed that cathepsin S inhibition stimulates the activation of a potent anti-tumor immune response and enhances the therapeutic efficacy of current immunotherapies. Thus, inhibition of cathepsin S could represent a novel and promising therapeutic strategy for FL treatment. In follow-up studies, we are identifying specific cathepsin S inhibitors with potential clinical applications.