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Aayushi Velingkar 1, Ramita Sharma 1, Priyanka Tiwari 2, Manasi Mundada 3, Rohan Tewani 4, Dylan T. Jochum 5, Rashid Mir 6, Faiq Ahmed 3, Sugunakar Vuree 1, Gopal Gopisetty 1, Senthil J. Rajappa 4, Aisha Ahmad Al-Khinji 7, Mallick Saumyaranjan 8, Chengfeng Bi 9,* and Waseem G. Lone 1,5, *  \nAcademic Editor: Alessandro Poggi  \nReceived: 2 May 2026  \nRevised: 22 June 2026  \nAccepted: 25 June 2026  \nPublished: 30 June 2026  \nCopyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \n1 Indo-American Cancer Research Foundation, Basavatarakam Indo-American Cancer Hospital and Research Institute, Banjara Hills, Hyderabad 500034, India; [ramita.bioinfo11@gmail.com](ramita.bioinfo11@gmail.com) (R.S.)  \n2 Department of Molecular Medicine, Jamia Hamdard, New Delhi 110062, India; [priyankatiwari6219@gmail.com](priyankatiwari6219@gmail.com)  \n3 Department of Hemato-Oncopathology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Banjara Hills, Hyderabad 500034, India  \n4 Medical Oncology, Basavatarakam Indo-American Cancer Hospital and Research Institute, Banjara Hills, Hyderabad 500034, India  \n5 Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA  \n6 Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk, Tabuk 71491, Saudi Arabia  \n7 Department of Genetics, Basic Medical Sciences, Qatar University, Doha 2713, Qatar  \n8 Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India  \n9 Division of Oncology & Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA  \n* Correspondence: [andy.bi@unmc.edu](andy.bi@unmc.edu) (C.B.); drwaseemlone@basavatarakam.org or [gullonewaseem@gmail.com](gullonewaseem@gmail.com) (W.G.L.)  \nAbstract  \nDiffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous mature B-cell neoplasm whose classification, prognosis, and therapy have been reshaped by advances in genomic, transcriptomic, epigenomic, single-cell, and spatial profiling technologies. This review focuses on how these approaches have refined the molecular landscape of DLBCL, including recurrent chromosomal translocations, tumor-suppressor alterations, oncogenic signaling pathways, and tumor-microenvironment programs. Cell-of-origin (COO) frameworks remain clinically useful. However, contemporary models extend beyond conventional germinal center categories by incorporating probabilistic genetic subtypes, expression-defined high-risk states, and spatially resolved lymphoma-cell and immune-cell ecosystems. These high-resolution methods clarify intratumoral heterogeneity, identify biologically distinct subgroups, and inform prognosis and therapeutic selection. The review also summarizes how tumor-intrinsic biology and the tumor-microenvironment (TME) shape responses to frontline therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, and CD19-directed CAR T-cell therapy. Particular emphasis is placedon product-specific evidence in relapsed/refractory disease, rational sequencing of immunotherapies, and emerging biomarkers such as circulating tumor DNA-based measurable residual disease (ctDNA-MRD) . Together, these developments support a shift from COO-centric classification toward dynamic, biology-driven models that incorporate tumorintrinsic and microenvironmental determinants to guide personalized therapy in DLBCL.  \nKeywords: diffuse large B-cell lymphoma; cell-of-origin classification; genomic profiling; tumor microenvironment; personalized therapy; circulating tumor DNA  \n1. Introduction  \nThe germinal center (GC) reaction, a dynamic process occurring within secondary lymphoid organs, is ch","cbCaimnDSg0X1muP","https://ap.wps.com/l/cbCaimnDSg0X1muP","pdf",7320832,23,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"What data types are emphasized for profiling diffuse large B-cell lymphoma in this review?\",\"answer\":\"The review emphasizes genomic, transcriptomic, epigenomic, single-cell, and spatial profiling technologies to reshape the molecular understanding of DLBCL.\"},{\"question\":\"How does the review describe the role of cell-of-origin frameworks in DLBCL?\",\"answer\":\"Cell-of-origin (COO) frameworks remain clinically useful, but contemporary models extend beyond classic germinal-center categories by incorporating probabilistic genetic subtypes and expression-defined high-risk states.\"},{\"question\":\"Which treatment response determinants are discussed for linking biology to therapy in DLBCL?\",\"answer\":\"The review summarizes how tumor-intrinsic biology and tumor microenvironment (TME) programs influence responses to frontline therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, and CD19-directed CAR T-cell therapy.\"}]","Diffuse Large B-Cell Lymphoma - From Molecular Stratification to Precision Immunotherapy | PDF",1790142043,58]