Targeting signaling pathways in lymphoma: From molecular mechanisms to clinical breakthroughs

The treatment paradigm for lymphoma, a highly heterogeneous group of hematologic malignancies, has been revolutionized by the development of therapies targeting oncogenic signaling pathways. This shift from conventional chemotherapy to precision medicine is driven by a deep molecular understanding of the pathways that govern lymphoma cell survival and proliferation. This review comprehensively surveys the landscape of these targeted therapies, from fundamental molecular mechanisms to clinical breakthroughs. We first dissect the molecular architecture of key oncogenic drivers, covering foundational survival networks such as the B-cell receptor, phosphatidylinositol 3-kinase /protein kinase B/mammalian target of rapamycin, Janus kinase/signal transducer and activator of transcription, and B-cell lymphoma 2 apoptosis pathways; critical regulatory processes like nuclear export controlled by exportin 1 and epigenetic patterns. For each therapeutic class, we discuss the clinical development of specific inhibitors and the challenge of acquired resistance. Furthermore, we examine emerging concepts in lymphoma, including the context-dependent role of the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes pathway, to provide a comprehensive overview of the current therapeutic landscape. A central theme of this review is the integration of these targeted agents into clinical practice. We discuss how the successful targeting of oncogenic signaling pathways has enabled the development of effective chemotherapy-free regimens, which offer durable responses with reduced toxicity and improved quality of life. Although initially transformative for patients with indolent lymphomas or those unfit for intensive chemotherapy, this paradigm is now extending to aggressive lymphomas as well. Another pivotal advance is the use of molecular subtyping and predictive biomarkers to guide treatment. As powerfully demonstrated by recent clinical trials, aligning targeted agents with the specific signaling or epigenetic dependencies of a tumor subtype can significantly enhance the efficacy of standard immunochemotherapy backbones in both B-cell and T-cell lymphomas. Finally, we address the persistent challenges of acquired resistance and discuss future directions, including the development of next-generation agents such as proteolysis-targeting chimeras, the design of rational, synergistic combination strategies, and the leveraging of multiomics and artificial intelligence to decipher complex signaling networks. By continuing to translate molecular insights into clinical practice, the field is steadily moving toward the goal of achieving precision cures for patients with lymphoma.