Diffuse Large B cell lymphoma (DLBCL) is the most common lymphoma with significant molecular heterogeneity within morphologically indistinguishable tumors of the lymph node. Two subtypes of DLBCL have remarkably poor clinical outcomes: the recently defined extranodal class of activated B cell-like (ABC)-DLBCL and the epigenetic class of germinal center B cell (GCB)-DLBCL (1, 2). The mechanism through which DLBCLs, and potentially other lymphomas, are resistant to current therapies are unknown but may be linked to the particular spectrum of somatic mutations in these tumors, which are in concert with complex growth signals provided by the malignant lymph node tumor microenvironment (Ly-TME). Many of the hallmark ABC-DLBCL mutations result in constitutive activation of protein components of B cell receptor (BCR) and Toll-like receptor (TLR) pathways in these malignant immune cells. Hence these pathways are emerging as a source of therapeutic targets for the treatment of ABC-DLBCLs. However, to date, existing BCR pathway inhibitors such as those targeting Bruton's tyrosine kinase are active in a limited subset of patients and only for a short duration, the causes of which are unknown. The substantial differences in response rates and response duration between ABC-DLBCL patients reflect the variable dependencies on BCR and TLR signaling and/or differential regulation by the Ly-TME. Unfortunately, we do not understand the impact of Ly-TME on cooperative, feed-back, and bypass signaling pathways in ABC-DLBCLs and, consequently, on the efficacy of inhibitors and/or agonists to adequately suppress these networks. A major limitation in the field has been the lack of an experimental therapeutics platform that recapitulates human cell and extracellular matrix components of Ly-TME, fluid characteristics and tissue stiffness that regulate DLBCL signaling, and also could model BCR- Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) paracaspase and TLR signaling cross-talk. In this talk, we will discuss the discoveries enabled by designer lymphoid organoids and on-chip technologies in understanding the epigenetic switches such as enhancer of zeste homolog 2 (EZH2) and components of the B Cell receptor signaling pathway that have emerged as key therapeutic targets in DLBCLs (3-6). We will also discuss the ongoing development of a more accurate 3D on-chip model and test the cooperative signaling between BCR-MALT1-TLR as well as the therapeutic efficacy of select inhibitors alone or in combination with other drugs. Research funding: The authors acknowledge financial support from the National Institutes of Health (1R33CA212968-01 to A.S) and Department of Defense Career Development Award (W81XWH-17-1-0215to A.S.).