Researchers from the Sant Pau Research Institute (IR Sant Pau) and CIBER-BBN have led an exhaustive scientific review of therapies aimed at the CXCR4 receptor, a key target in more than 20 types of cancer. The article, published in Biomarker Research, provides a comprehensive overview of the most advanced therapeutic and diagnostic approaches under development to act on this receptor, considered a poor-prognosis biomarker and a characteristic signature of tumor stem cells.
The CXCR4 receptor (C-X-C chemokine receptor type 4) is a membrane protein belonging to the family of G-protein-coupled receptors whose normal role is to guide cell migration, especially in the immune system and during embryonic development. Under physiological conditions it regulates processes such as hematopoiesis, tissue regeneration, and the inflammatory response, acting as a cellular docking site for its natural ligand, the chemokine CXCL12. However, this essential function becomes corrupted in pathological contexts such as cancer, where CXCR4 overexpression in tumor cells gives them advantages such as the ability to invade tissues, evade the immune system, and resist treatments.
Beyond its physiological role, CXCR4 has for decades been an object of interest in HIV research because the virus uses it as a co-receptor to enter certain immune cells. This intense work in the context of HIV infection made it possible to characterize its structure, develop multiple antagonists, and deepen our understanding of its activation mechanisms—knowledge that is now being repurposed in oncology.
“The CXCR4 receptor has proved to be an extraordinary molecular target for precision oncology. Its overexpression in many tumor types makes it a strategic target both for blocking cancer progression and for accurately delivering drugs to the most aggressive tumor cells,” emphasizes Dr. Ugutz Unzueta, researcher in the Oncogenesis and Antitumor Drugs group and coordinator of the review.
The IR Sant Pau group has been at the forefront of this line of research for the past fifteen years, with more than one hundred publications focused on developing nanomedicine based on protein nanoparticles that selectively recognize and attack CXCR4⁺ cells. Their approach has contributed significantly to expanding the therapeutic arsenal available against resistant tumors or those with a high risk of metastasis. This accumulated experience was decisive in leading a review that summarizes current knowledge and outlines future directions in the clinical development of this strategy.
CXCR4 has been extensively validated as a therapeutic target. Developing new strategies therefore faces the challenge of improving efficacy without increasing toxicity, giving prominence to approaches that allow targeted, selective drug delivery. Designing functionalized nanoparticles, antibody-drug conjugates, photothermal molecules, or interfering RNA’s specifically aimed at CXCR4-positive cells opens new avenues to increase specificity and reduce adverse effects.
Looking ahead, prospects point to closer integration of diagnosis, patient selection, and treatment. Precision cancer medicine is moving toward combination therapies able to simultaneously recognize multiple tumor markers—such as CXCR4 together with others typical of tumor stem cells—helping overcome one of today’s main challenges: tumor plasticity and heterogeneity within the same tumor.
The review also argues for redesigning clinical trials. Instead of traditional models focused on specific tumor types, the authors highlight the value of so-called basket trials, which group patients by shared biomarkers—such as high CXCR4 expression—regardless of the tumor’s organ of origin. This approach would enable better patient selection and higher therapeutic response rates.
Meanwhile, molecular imaging technologies such as positron emission tomography (PET) with specific tracers are poised to play a fundamental role in patient detection, stratification, and monitoring. Agents like [68Ga]-Pentixafor allow non-invasive visualization of CXCR4 expression in tumors and target organs, facilitating both the selection of candidates for targeted therapies and real-time monitoring of response.
“Progress in personalized medicine for cancer treatment demands combining imaging technologies, molecular markers, and targeted therapies. CXCR4 is a paradigmatic example of how basic and applied research can converge to change clinical practice,” notes Ariana Rueda, first author of the study.
Rueda A, Serna N, Mangues R, Villaverde A, Unzueta U. Targeting the chemokine receptor CXCR4 for cancer therapies. Biomarker Research. 2025;13:68. https://doi.org/10.1186/s40364-025-00778-y.
