Common Sunscreen Chemical Benzophenone-1 Reprograms Immune Cells to Fuel Breast Cancer Growth in Lab Study

A chemical routinely added to cosmetics and personal care products to soak up ultraviolet radiation may do far more than shield the skin from the sun. In a new study published in Frontiers in Molecular Biosciences, researchers in China report that benzophenone-1, or BP-1, can reprogram immune cells called macrophages in ways that make breast cancer cells grow faster, move farther, and invade more aggressively in laboratory experiments. The finding shifts attention from the chemical’s well-known estrogenic effects on tumor cells themselves to a quieter, potentially more insidious route of influence: the tumor microenvironment.

BP-1, chemically known as 2,4-dihydroxybenzophenone, belongs to a family of hydroxylated benzophenone compounds used as ultraviolet absorbers and photostabilizers in cosmetic formulations. Because these products are applied directly to the skin and often remain there for hours in leave-on preparations, dermal uptake is a realistic exposure route. The molecule is small, with a molecular weight of 214.22 grams per mole and moderate lipophilicity, and safety assessments by the Scientific Committee on Consumer Safety suggest it has a low to moderate potential for dermal absorption. Worryingly, human biomonitoring studies have detected BP-1 in maternal serum, amniotic fluid, and fetal and cord blood samples, indicating that the compound crosses biological barriers that many toxicologists once assumed were protective.

Structurally, BP-1 carries phenolic hydroxyl groups on aromatic rings, features that allow it to interact with hormone-responsive cellular systems. Previous work has shown that the position and number of these hydroxyl substituents influence the estrogenic activity of benzophenone derivatives, and some members of the family also exhibit anti-androgenic activity. Earlier studies established that BP-1 induces estrogen-like responses in estrogen receptor-positive breast cancer models, including changes in estrogen-responsive transcription, cell proliferation, cell cycle gene expression, and metastasis-associated genes. Beyond endocrine disruption, BP-1 has been linked to intracellular reactive oxygen species accumulation, impaired antioxidant defenses, and mitochondrial and nuclear injury, raising the possibility of DNA damage and genomic instability.

To move beyond these tumor-cell-intrinsic effects, the research team, led by investigators at the Fourth Affiliated Hospital of Hebei Medical University, assembled a multi-layered analytical pipeline. They merged three breast cancer transcriptomic datasets from the Gene Expression Omnibus database, corrected batch effects, and identified 1,549 differentially expressed genes between tumor and normal tissue. Weighted gene co-expression network analysis then pinpointed a module of 85 genes most strongly associated with breast cancer, yielding a combined set of 1,597 breast cancer-related genes. In parallel, they predicted BP-1’s molecular targets using three databases, ChEMBL, the Similarity Ensemble Approach, and SwissTargetPrediction, which together yielded 107 BP-1-associated targets. Fifteen of these overlapped with the breast cancer gene set, forming the candidate pool for deeper interrogation.

The decisive step came from machine learning. The team applied four independent feature-selection algorithms, least absolute shrinkage and selection operator regression, support vector machine recursive feature elimination, XGBoost, and Boruta, to the 15 candidates. Only one gene survived all four filters: PLAUR, the gene encoding the urokinase-type plasminogen activator receptor, or uPAR. Single-cell RNA sequencing of a breast cancer dataset revealed that PLAUR was prominently expressed in macrophage, epithelial, and fibroblast clusters, with macrophages standing out as a key site of expression. Virtual overexpression of PLAUR in disease-derived single cells, simulated through the scTenifoldNet framework, perturbed genes involved in peptidase regulation, focal adhesion, cell-substrate junctions, and collagen-containing extracellular matrix, processes intimately tied to invasion and metastasis.

Molecular docking predicted that BP-1 binds uPAR with a binding energy of minus 6.9 kilocalories per mole, forming hydrogen bonds, pi interactions, and van der Waals contacts within the protein’s binding pocket. A 100-nanosecond molecular dynamics simulation confirmed the stability of this complex: the root-mean-square deviation plateaued between 0.6 and 0.9 nanometers, the radius of gyration held steady at roughly 2.2 to 2.4 nanometers, and the free energy landscape displayed a prominent low-energy basin. In the TCGA breast cancer cohort, PLAUR expression was markedly higher in tumors than in normal tissue, with an area under the receiver operating characteristic curve of 0.885, and high-PLAUR tumors were enriched in immune and inflammatory signaling, antigen processing, and cell migration pathways.

With the computational evidence in hand, the researchers turned to the laboratory. They differentiated human THP-1 monocytes into macrophages and exposed them to BP-1 at 1 and 10 micromolar concentrations, both well below the compound’s half-maximal inhibitory concentration of 118.5 micromolar in these cells. Within 48 hours, the macrophages underwent a striking transformation. Western blotting showed that uPAR protein expression increased with BP-1 concentration. Immunofluorescence revealed a decline in CD86, a marker of inflammatory M1 macrophages, and a rise in CD206, a hallmark of the alternatively activated M2 phenotype. At the messenger RNA level, CD163, CD206, and TGFB1 all increased, while CD86 and tumor necrosis factor decreased. Enzyme-linked immunosorbent assays confirmed that the treated macrophages secreted more interleukin-10 and transforming growth factor beta 1, both signature cytokines of the M2-like, tumor-supportive state.

The critical experiment followed. The team collected conditioned medium from BP-1-treated macrophages and applied it to two estrogen receptor-positive breast cancer cell lines, MCF-7 and T-47D. The results were unambiguous. EdU incorporation assays showed a significant increase in DNA synthesis, colony formation assays demonstrated enhanced long-term proliferative capacity, and Transwell and wound healing assays revealed accelerated migration. In MCF-7 cells, Matrigel-coated invasion assays showed a heightened ability to breach extracellular matrix barriers. Western blotting then uncovered the molecular signature underlying these behaviors: the epithelial marker E-cadherin decreased, while the mesenchymal markers N-cadherin and vimentin and the transcription factor Snail all increased, a classic epithelial-mesenchymal transition profile. Crucially, when the researchers added BP-1 directly to conditioned medium from untreated macrophages, the proliferative and motility effects persisted, but the EMT-related protein changes did not appear, suggesting that the macrophage secretome, rather than the chemical alone, drives the transition program.

The mechanism likely centers on TGF-beta 1, which the BP-1-treated macrophages secreted at elevated levels. Upon binding its receptor, TGF-beta 1 triggers phosphorylation of SMAD2/3, which associates with SMAD4 and induces EMT-related transcription factors such as Snail, which in turn represses E-cadherin. TGF-beta 1 also activates non-SMAD pathways, including MAPK, PI3K/AKT, and Rho GTPases, that govern cytoskeletal organization and cell motility. Previous studies have shown that macrophage-conditioned medium can induce TGF-beta-dependent EMT in MCF-7 cells, and that uPAR-integrin signaling promotes breast cancer invasion through the extracellular matrix. The new findings slot neatly into this framework, positioning PLAUR/uPAR as a candidate molecular bridge between BP-1 exposure, macrophage reprogramming, and malignant phenotypes in estrogen receptor-positive breast cancer.

The authors are careful to note the limitations of their work. The experiments relied on THP-1-derived macrophages and predominantly MCF-7 cells, and validation in primary macrophages and additional breast cancer models would strengthen generalizability. Estrogen receptor signaling was not examined with an antagonist or receptor knockdown, so its contribution to the observed responses remains undetermined. And uPAR and TGF-beta 1 emerged as potential mediators, but direct perturbation experiments, such as PLAUR knockdown or TGF-beta 1 neutralization, will be needed to confirm causality. Importantly, the researchers emphasize that sunscreen use remains vital for preventing ultraviolet damage and skin cancer, and they point to newer filters such as bemotrizinol, a photostable triazine compound with low systemic exposure, as promising alternatives. Yet they caution that improved photoprotection does not guarantee biological or environmental safety, and that the effects of new filters, their metabolites, and repeated exposure deserve rigorous evaluation before widespread adoption. For now, the study adds a new dimension to how scientists think about ultraviolet filters: not merely as molecules that touch tumor cells directly, but as agents capable of reshaping the immune landscape in which those tumors live and grow.

Subject of Research: Effects of the ultraviolet filter benzophenone-1 on macrophage polarization and malignant phenotypes in estrogen receptor-positive breast cancer cells

Article Title: Macrophage reprogramming by the ultraviolet filter benzophenone-1 promotes malignant phenotypes in breast cancer cells: integrated computational and experimental evidence

Article References: He, B., Ding, L., Yang, X., Zhang, T., & Ma, L. (2026). Macrophage reprogramming by the ultraviolet filter benzophenone-1 promotes malignant phenotypes in breast cancer cells: integrated computational and experimental evidence. Frontiers in Molecular Biosciences, 13, Article 1946836. https://doi.org/10.3389/fmolb.2026.1946836

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1946836

Keywords: benzophenone-1, breast cancer, macrophage polarization, PLAUR, uPAR, ultraviolet filters, tumor microenvironment, epithelial-mesenchymal transition, endocrine disruption, TGF-beta 1, Macrophage, reprogramming