Lymphoma resistance mechanisms and future therapies

A new review was published in Volume 12 of Oncoscience on October 13, 2025, titled "Targeted therapies and resistance mechanisms in lymphoma: Current landscape and emerging solutions."

In this article by Bishal Tiwari, Roshan Afshan and Shruthi Sridhar, from Nassau University Medical Center and Detroit Medical Center Wayne State University, researchers reviewed the latest scientific findings on how lymphomas develop resistance to modern cancer therapies. The work outlines how these blood cancers adapt to evade treatment and discusses new strategies under investigation to restore treatment effectiveness. 

Lymphomas are among the most common blood cancers worldwide. Recent advances in targeted therapies, including monoclonal antibodies, CAR T-cell therapy, and immune checkpoint inhibitors, have led to major improvements in outcomes. These treatments work by attacking specific markers or pathways found in cancer cells. Yet despite initial success, many patients experience relapse when the cancer finds ways to resist or escape therapy.

The review highlights four key resistance mechanisms: loss of the target antigen (such as CD19 or CD20), reactivation of growth and survival pathways through mutations, changes in the tumor microenvironment that suppress immune responses, and genetic alterations that allow cancer cells to avoid cell death. These biological changes make it difficult for standard therapies to maintain long-term control of the disease.

"We comprehensively evaluate FDA-approved targeted agents, including monoclonal antibodies (rituximab, brentuximab vedotin, obinutuzumab, mogamulizumab), immune checkpoint inhibitors (nivolumab, pembrolizumab), CAR T-cell therapies (axi-cel, tisa-cel, liso-cel, brexu-cel), bispecific T-cell engagers (mosunetuzumab, epcoritamab), and small-molecule inhibitors (ibrutinib, idelalisib, venetoclax)."

To address this problem, researchers are exploring new treatment approaches. These include using drugs in combinations that block multiple pathways at once, creating CAR T cells that recognize more than one antigen, and developing next-generation antibody therapies. The review also discusses the promise of biomarker-guided therapy, which uses molecular testing to select the most effective treatments based on the unique characteristics of a patient's cancer.

One of the emerging strategies discussed is the use of "dual-target" therapies that make it difficult for lymphoma cells to escape. Other approaches aim to boost the immune system's ability to fight back, or to re-sensitize tumors that have become resistant. Some of these solutions are already being tested in clinical trials, while others are still in development.

Overall, this review provides a comprehensive overview of the challenges facing current lymphoma treatments and the innovations aimed at overcoming them. By focusing on both the causes of drug resistance and potential solutions, the article serves as a valuable resource for clinicians, researchers, and healthcare professionals working to improve outcomes for patients with difficult-to-treat lymphoma.