The rationale behind the design lies in one of the most stubborn problems in modern cancer imaging and treatment: heterogeneity. Tumors are not uniform masses of malignant cells but complex ecosystems in which cancer cells are interwoven with stromal cells, immune infiltrates, and a remodeled extracellular matrix. Cancer-associated fibroblasts, which are abundant in many solid tumors and can be identified by their expression of fibroblast activation protein, have become a favored target for theranostic agents because they are present across a wide range of tumor types. At the same time, integrin αvβ3, a receptor that promotes angiogenesis and metastatic behavior, is overexpressed on both certain tumor cells and activated endothelial cells within the tumor vasculature. By targeting both markers with a single molecule, the researchers aimed to increase the fraction of injected radioactivity that reaches and stays within the tumor, rather than relying on a single receptor whose expression may vary widely from patient to patient or even from lesion to lesion within the same patient.

The team, led by researchers from Nanchang University, Southern Medical University, and Harbin Medical University Cancer Hospital, synthesized a series of three candidate compounds, INN01 through INN03, by conjugating a potent boronic acid-based FAP inhibitor motif to either RGDyK or RGDfK cyclic peptides through a DOTA chelator capable of holding both gallium-68 and lutetium-177. In vitro binding assays using A549 cells engineered to express FAP showed that all three heterodimers retained nanomolar affinity for FAP, with IC50 values of 1.28 ± 0.14 nanomolar for INN01, 2.86 ± 0.83 nanomolar for INN02, and 1.07 ± 0.35 nanomolar for INN03. Cellular uptake, internalization, efflux, and blocking experiments performed in U87MG cells, a line known to express integrin αvβ3, allowed the investigators to compare how each construct behaved once bound to its targets and to confirm that uptake could be displaced by excess cold ligand, a hallmark of receptor-specific binding.

When the three candidates were labeled with gallium-68 and tested in mice bearing U87MG tumors, INN02 emerged as the clear frontrunner. Sixty minutes after injection, [68Ga]Ga-INN02 achieved a tumor uptake of 11.65 ± 2.21 percent of the injected activity per gram of tissue, roughly six times higher than the 1.91 ± 1.10 percent measured for [68Ga]Ga-PNT6555, a comparator radiotracer used as a benchmark in the same model. The compound also cleared from the body predominantly through the kidneys, a pharmacokinetic profile that is generally desirable for imaging agents because it limits radiation exposure to the liver and intestines and reduces the likelihood of abdominal background signal that can obscure lesions. Small-animal PET/CT scans confirmed that the high tumor uptake translated into high-contrast images in which tumors stood out clearly against surrounding tissue.

The therapeutic potential of the scaffold was then tested by swapping the imaging isotope for the beta-emitting therapeutic radionuclide lutetium-177. In the same U87MG tumor model, [177Lu]Lu-INN02 reached an early tumor uptake of 21.96 ± 3.09 percent of the injected activity per gram at one hour after injection, compared with 12.98 ± 5.19 percent for [177Lu]Lu-PNT6555, and it showed lower exposure in the liver and blood. Lower off-target accumulation matters enormously in radioligand therapy because the dose that can safely be administered is constrained by the radiation delivered to healthy organs, particularly the kidneys and bone marrow. A probe that concentrates more of its payload in the tumor and less in critical normal tissues can, in principle, deliver a more effective tumoricidal dose within the same safety envelope.

To evaluate efficacy, the researchers treated groups of eight to ten tumor-bearing mice with a single 37-megabecquerel dose of [177Lu]Lu-INN02 and followed tumor growth and survival. By day fourteen, tumors in the treated animals measured 583 ± 338 cubic millimeters on average, compared with 1130 ± 424 cubic millimeters in saline-treated controls, a difference that reached statistical significance with a p-value of 0.030. Median survival was prolonged from sixteen days in the control group to twenty days in the treated group. Importantly, no overt acute toxicity was observed under the conditions tested, although the authors note that the study examined a single-dose regimen and that the safety margins observed in mice will need to be confirmed in larger and longer studies before the compound could advance toward routine clinical use.

The most eye-catching part of the study for clinicians may be the pilot prospective clinical evaluation of [68Ga]Ga-INN02 PET/CT, which enrolled six patients under a trial registered with the Chinese Clinical Trial Registry in March 2022. In these first-in-human images, the tracer demonstrated high uptake in tumor lesions with low background signal across multiple cancer types, allowing clear visualization of both primary tumors and metastatic deposits. Because FAP is expressed by stromal cells rather than by the cancer cells themselves, FAP-targeted imaging has the potential to reveal the full extent of the desmoplastic reaction surrounding a tumor, information that can complement conventional anatomical imaging and other molecular tracers. Adding the integrin αvβ3 component may further broaden sensitivity by flagging tumor cells and newly forming blood vessels that the FAP motif alone would miss.

The theranostic pairing at the heart of the work reflects a broader trend in nuclear medicine, in which the same targeting molecule is labeled with a diagnostic isotope for patient selection and staging and with a therapeutic isotope for treatment, an approach that has already transformed the management of prostate cancer through prostate-specific membrane antigen-targeted radioligand therapy. Gallium-68, with its 68-minute half-life and positron emission, is ideal for same-day PET imaging, while lutetium-177, with a half-life of about 6.7 days and beta emissions that travel a few millimeters in tissue, can irradiate tumor cells while sparing nearby normal tissue. A single precursor molecule that accommodates both isotopes through the same DOTA chelator streamlines manufacturing and regulatory development, because the imaging and therapeutic agents share an identical targeting vector and can be produced from the same chemical intermediate.

The authors are careful to frame the findings as early-stage but encouraging. The clinical component involved only six patients and was designed as a proof-of-concept rather than a definitive assessment of diagnostic accuracy, and the therapy experiments were conducted in a single xenograft model with a single dose level. Heterodimeric constructs also carry inherent design trade-offs: linking two targeting motifs increases molecular size, which can alter pharmacokinetics, and the relative contribution of each receptor to total tumor uptake remains difficult to disentangle without dedicated blocking studies in vivo. Nevertheless, the magnitude of the uptake improvement over the comparator tracer, the favorable renal clearance, and the statistically significant tumor growth inhibition together provide a strong foundation for the further clinical evaluation that the authors say the results support.

If larger studies replicate these findings, dual-target radioligands of this kind could expand the reach of theranostics beyond the tumor types where single-target agents have so far performed best, offering clinicians a way to image and then treat tumors whose stromal and vascular landscapes vary from patient to patient. The work also illustrates how rational molecular design, combining well-validated targeting motifs with established chelation chemistry, can yield compounds that move from bench to first-in-human imaging within a few years. For a field in which the difference between a clear image and a blurry one, or between tumor control and progression, often comes down to how much radioactivity reaches the right cells, INN02’s sixfold advantage in tumor uptake is a result that radiologists, nuclear medicine physicians, and oncologists alike will be watching closely as the compound advances through the clinical pipeline.

Subject of Research: Development of a dual-targeted FAP/integrin αvβ3 heterodimeric radioligand for PET imaging and radionuclide therapy of cancer

Article Title: Design and evaluation of a FAP/αvβ3 dual-targeted 68Ga/177Lu heterodimeric radioligand for cancer theranostics

Article References: Sun, M., Feng, D., Li, X., Chen, B., Li, H., Yang, R., Peng, S., Cheng, L., Zhao, Y., Liu, W., Cao, Q., Wang, K., & Hu, K. (2026). Design and evaluation of a FAP/αvβ3 dual-targeted 68Ga/177Lu heterodimeric radioligand for cancer theranostics. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09034-9

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09034-9

Keywords: fibroblast activation protein, integrin αvβ3, heterodimeric radioligand, theranostics, PET imaging, lutetium-177, gallium-68, radioligand therapy, tumor microenvironment, cancer-associated fibroblasts, molecular imaging, nuclear medicine