AccScience Publishing / ARNM / Online First / DOI: 10.36922/ARNM025480061
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REVIEW ARTICLE

CXCR4-targeted theranostics in non-Hodgkin lymphoma: Present evidence and future directions

Marcus Yoakam1 ,  Uma A. Obalapuram1 ,  Kameron Hahn1 ,  Samir Dalia2*
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1 Department of Medical Education, College of Osteopathic Medicine, Kansas City University, Joplin, Missouri, United States of America
2 Department of Medical Oncology, Mercy Hospital, Joplin, Missouri, United States of America
ARNM, 025480061 https://doi.org/10.36922/ARNM025480061
Received: 30 November 2025 | Revised: 19 December 2025 | Accepted: 9 January 2026 | Published online: 27 January 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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Abstract

Non-Hodgkin lymphoma (NHL) is a biologically heterogeneous group of lymphoid malignancies with variable clinical outcomes despite advances in chemotherapy, immunotherapy, and cellular therapies. The C–X–C chemokine receptor 4 (CXCR4)/ C–X–C motif chemokine ligand 12 (CXCL12) axis plays a central role in lymphocyte trafficking, survival, and tumor microenvironment interactions. It is frequently dysregulated in NHL, making it an attractive target for precision oncology. CXCR4- directed theranostics combines molecular imaging and targeted radionuclide therapy, enabling real-time assessment of receptor expression, patient stratification, and personalized treatment delivery. Diagnostic positron emission tomography imaging using 68Ga-pentixafor reliably visualizes CXCR4-expressing disease, while therapeutic agents, such as 177Lu- or 90Y-pentixather and CXCR4-targeted antibody– drug conjugates demonstrate selective tumor targeting and potent cytotoxicity in preclinical and early clinical studies. Despite promising antitumor activity and manageable toxicity, several challenges remain, including heterogeneous and dynamically regulated CXCR4 expression, protective microenvironmental niches, hematologic toxicity, radiopharmaceutical limitations, and infrastructural requirements for widespread clinical implementation. Ongoing research is focused on optimizing dosing, refining patient selection, combining CXCR4-targeted therapies with other modalities, and expanding clinical trials to establish efficacy and safety. CXCR4 theranostics holds substantial potential to improve precision management of NHL by integrating diagnostic and therapeutic modalities into a unified, patient-tailored approach.

Keywords
Thernostics/Theragnostics
C–X–C chemokine receptor 4
Non-Hodgkin lymphoma
68Ga-pentaxifor
177Lu-pentixather
Radioligand therapy
Funding
None.
Conflict of interest
The authors declare that they have no competing interests.
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