Twenty-four hours after reperfusion began, the treated mice fared measurably better than untreated controls. Echocardiography showed improved cardiac function, and TTC/Evans Blue staining revealed smaller infarcts. Levels of lactate dehydrogenase and creatine kinase-MB were significantly reduced in the blood of treated animals, and histopathological analysis of the heart tissue corroborated the functional and biochemical signs of protection.

The immunological signature of the treated hearts shifted consistently. Pro-inflammatory cytokines TNF-α, IL-6, and IL-1β dropped in both serum and cardiac tissue, while the anti-inflammatory cytokines IL-10 and TGF-β rose. The inflammatory M1 macrophage marker iNOS was downregulated in cardiac tissue, whereas the M2 marker Arg-1 was upregulated, indicating a shift in macrophage polarization toward the repair-associated M2 phenotype in the injured myocardium.

To probe the mechanism, the team turned to bone marrow-derived macrophages grown in culture. When exposed to rEgAgB8/2, the cells secreted a cytokine profile matching the in vivo observations and showed reduced activation of the cGAS–STING pathway, an intracellular sensor system that signals through the proteins TBK1 and IRF3 to drive inflammatory responses. Flow cytometry identified M1 cells by the surface marker CD86 and M2 cells by CD206, and the treated macrophages showed enhanced polarization toward the M2 phenotype.

Western blotting of both myocardial tissue and cultured macrophages demonstrated lower levels of proteins in the cGAS/STING/p-TBK1/p-IRF3 signaling pathway after treatment, linking the parasite protein's effect directly to this innate immune signaling axis in the same animals and cells where protection and polarization were measured. The authors conclude that rEgAgB8/2 promotes macrophage polarization toward the M2 phenotype in a manner associated with suppression of the cGAS/STING/TBK1/IRF3 pathway, thereby attenuating myocardial ischemia–reperfusion injury and the associated inflammation. They frame the result as a potential novel therapeutic strategy for reperfusion injury and related inflammatory diseases.

Important caveats remain. The work was conducted in mice with a single twenty-four-hour reperfusion timepoint, and the protein was delivered intraperitoneally. Within this short-term model the study shows that pathway suppression, macrophage polarization, and tissue protection occurred together, and the shared version of the article is an accepted manuscript subject to further editorial processing.

The findings are preclinical and do not yet establish any benefit for human patients.

Subject of Research: Recombinant Echinococcus granulosus antigen B8/2 modulation of the macrophage cGAS–STING pathway in mouse myocardial ischemia–reperfusion injury

Article Title: Echinococcus granulosus antigen B regulates the macrophage cGAS–STING pathway to mitigate myocardial ischemia–reperfusion injury

Article References: Wang, S., Chen, F., Luo, Y., Jin, Q., Li, H., Li, H., Yang, C., Li, X., Wang, W., Gao, E., Chu, L., Qiu, Y., Zhou, R., & Yang, X. (2026). Echinococcus granulosus antigen B regulates the macrophage cGAS–STING pathway to mitigate myocardial ischemia–reperfusion injury. Parasites & Vectors. https://doi.org/10.1186/s13071-026-07653-1

Image Credits: AI Generated

DOI: 10.1186/s13071-026-07653-1

Keywords: Echinococcus granulosus, antigen B, cGAS-STING, macrophage polarization, M2 macrophages, myocardial ischemia-reperfusion injury, inflammation, cytokines, preclinical study, immunomodulation, Echinococcus, granulosus

M6A is the most abundant internal modification found in the RNA of eukaryotic cells. It involves the addition of a methyl group to the sixth nitrogen atom of adenine, and it appears not only on messenger RNA but also on transfer RNA, ribosomal RNA, microRNA, circular RNA and long noncoding RNA. The mark changes the fate of the molecules that carry it, affecting splicing, export from the nucleus, stability, translation and the production of microRNAs. Because of this reach, m6A has been implicated in embryonic development, cancer and neurodegeneration, and a growing body of work now connects it to cardiovascular disease, including the formation, progression and rupture of aortic dissection.

The modification is controlled by three classes of proteins. Writers, led by the METTL3-METTL14-WTAP complex, install the methyl marks; METTL3 acts as the catalytic subunit while METTL14 improves substrate recognition and WTAP anchors the complex in the nucleus. Erasers, principally FTO and ALKBH5, remove the marks, making the process reversible. Readers, including the YTH domain family and proteins such as IGF2BP1/2/3 and members of the HNRNP family, recognize methylated sites and determine the consequences for each RNA. When any of these regulators are misexpressed, the balance of RNA methylation across thousands of transcripts can shift, with effects that differ from one cell type to the next.

The review, written by a team of cardiothoracic surgery researchers in China, gathers evidence that m6A regulators behave abnormally in dissection and can either promote or restrain the disease depending on the transcript, the reader protein and the cell type involved. One of the clearest examples concerns cell death. In aortic tissue from patients, the writer KIAA1429 is decreased while the eraser ALKBH5 is increased. In mice infused with angiotensin II, restoring KIAA1429 promoted the conversion of pri-miR-143-3p into mature miR-143-3p in an m6A-dependent manner, which stimulated vascular smooth muscle cell proliferation, reduced endothelial cell apoptosis and eased the disease, whereas ALKBH5 overexpression produced the opposite effect.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has emerged as another m6A-controlled process in the aortic wall. METTL3 is upregulated in the aorta of patients with Stanford type A dissection and correlates negatively with SLC7A11 and FSP1, two proteins that suppress ferroptosis. Overexpressing METTL3 accelerated the decay of the mRNAs encoding these protective proteins in an m6A-dependent way, promoting ferroptosis in human arterial smooth muscle cells and worsening dissection in mice treated with beta-aminopropionitrile. Separately, METTL3 was reported to methylate the long noncoding RNA NORAD, lowering its expression through the reader YTHDF2; because NORAD normally stabilizes the mRNA for the antioxidant enzyme GPX4, its loss removes another brake on ferroptosis. The authors also describe evidence that METTL3 recruits YTHDF2 to destabilize NOTCH1 mRNA, pushing smooth muscle cells from a quiescent contractile state into a synthetic state that degrades the extracellular matrix, a hallmark step in wall weakening.

Immune mechanisms add a further layer. Macrophages in the aortic wall can polarize toward a pro-inflammatory M1 state or an anti-inflammatory M2 state, and dissection is generally associated with an M1 shift. The writer RBM15 is highly expressed in aortic tissue from patients with dissection, and in rat models its overexpression enhanced glycolysis by upregulating GLUT1 and HK2 in an m6A-dependent manner, driving macrophages toward the M1 phenotype and accelerating disease. Oxidative stress may also be involved: the reader YTHDC1 is reduced in aortic tissue from patients, and knocking it down in cultured endothelial cells increased reactive oxygen species production and lowered superoxide dismutase 2 expression, hinting at a protective role that has not yet been fully tested in animals.

The review extends the same logic to the major risk factors for dissection. Roughly 80 percent of patients who develop the condition are estimated to have hypertension, and METTL3 expression and global m6A levels are elevated in the arteries of hypertensive patients and angiotensin II-treated mice; methylating the ADAM17 mRNA promotes its export from the nucleus, cleavage of ACE2, vasoconstriction and higher blood pressure. In atherosclerosis, which affects about 31 percent of dissection patients, macrophage-specific deletion of METTL3 in mice reduced inflammatory signaling and plaque formation, while METTL14-driven methylation of FOXO1 and UCHL5 mRNAs aggravated endothelial inflammation. In obesity, m6A regulators including FTO, ALKBH5, METTL14 and IGF2BP3 modulate fat cell formation and the browning of white adipose tissue in animal studies. In aortic aneurysm, elevated global m6A levels and increased YTHDF3 expression track with disease severity, and METTL14 or WTAP promoted smooth muscle cell ferroptosis and apoptosis through methylated target mRNAs.

These converging findings suggest diagnostic and therapeutic possibilities, though the authors are careful to note how preliminary they remain. A database analysis found that the eraser FTO and the reader IGF2BP1 were dysregulated in dissection samples and showed relatively good accuracy in a diagnostic prediction model, but no m6A-based biomarker has been validated in prospective clinical studies. On the therapeutic side, small-molecule inhibitors already exist: STM2457, a first-in-class catalytic inhibitor of METTL3, has suppressed macrophage activation and plaque formation in atherosclerosis models and eased pulmonary arterial hypertension in experimental settings, while RSM3 and KH12 promote METTL3 degradation and the ALKBH5 inhibitor IOX1 protected against atherosclerosis in preclinical work. Natural compounds such as coptisine chloride and curcumin also modulate METTL3, and microRNAs including miR-145 and miR-186-5p, which target YTHDF2 and METTL3 respectively, have shown protective effects in dissection models.

None of these strategies has yet been tested in clinically relevant models of aortic dissection itself, and the review outlines substantial obstacles before any could reach patients. Because m6A decorates a vast range of RNA molecules, the specificity and safety of interventions are uncertain; systemic delivery risks off-target disruption of methylation in healthy tissues; cross-talk among different RNA modifications could produce unforeseen effects; and the feasibility of combining m6A-targeting drugs with standard treatments such as blood pressure control has not been assessed. Most mechanistic evidence rests on angiotensin II or beta-aminopropionitrile mouse models and cultured vascular smooth muscle cells, with human validation limited to small observational tissue samples. Even so, the picture that emerges is striking: a single, reversible chemical tag on RNA appears to sit at the junction of cell death, inflammation, oxidative stress and wall remodeling that together determine whether the aorta holds or tears. If future animal studies and early trials confirm the promise suggested by this early-phase research, the enzymes that write and erase m6A could become the first genuinely molecular drug targets for a disease that medicine has so far been able to treat only with a scalpel.

Subject of Research: The role of N6-methyladenosine RNA modification in the mechanisms and potential treatment of aortic dissection

Article Title: The emerging role of m6A in aortic dissection: from molecular mechanisms to therapeutic potential

Article References: She, C.-Q., Long, C.-Z., Lyv, X.-L., Lei, Z.-W., Kuang, W.-A., Deng, H., Yi, M.-L., Cai, S.-W., Yu, X.-H., Peng, Y., & Feng, Y.-G. (2026). The emerging role of m6A in aortic dissection: from molecular mechanisms to therapeutic potential. Frontiers in Cell and Developmental Biology, 14, Article 1906074. https://doi.org/10.3389/fcell.2026.1906074

Image Credits: AI Generated

DOI: 10.3389/fcell.2026.1906074

Keywords: aortic dissection, m6A, RNA modification, epigenetics, METTL3, ferroptosis, vascular smooth muscle cells, hypertension, atherosclerosis, macrophage polarization, aortic aneurysm, drug targets

The strategy, described as Immunometabolic–Hyperthermia Therapy, or IMHT, was tested in diabetic rats with infected defects in the femoral condyle. It rests on a dual-functional material: polydopamine nanoparticles loaded with itaconate, embedded in a gelatin–agarose hydrogel. Itaconate is an immunometabolite produced naturally by activated macrophages from the tricarboxylic acid cycle intermediate cis-aconitate, and it has attracted attention for its anti-inflammatory, antioxidant, and antimicrobial properties. Polydopamine, meanwhile, is a strong photothermal agent that converts near-infrared light into heat, giving the hydrogel a built-in heating element.

The therapeutic schedule is deliberately two-phased. On the first day after surgery, the implanted hydrogel is irradiated with an 808 nm near-infrared laser, driving the defect site to roughly 50 °C for ten minutes. This high-temperature phase is the primary antibacterial weapon: in vitro, heat alone visibly disrupted mature Escherichia coli biofilms, thinning and dispersing the dense bacterial architecture, while the itaconate released from the nanoparticles made a further but moderate contribution to killing. From day three onward, the regimen shifts gears, applying repeated sessions of mild hyperthermia at approximately 41 °C every two days for four weeks, alongside continuous itaconate release.

The material itself was engineered with care. Incorporating itaconate during in situ polymerization changed the supramolecular organization of the polydopamine particles, shifting their surface charge from −4.85 mV to nearly neutral and increasing their hydrodynamic diameter to about 540 nanometers, with a stable mesoporous, spherical structure that persisted over fourteen days in water and culture medium. High-performance liquid chromatography confirmed that the nanoparticles released itaconate continuously over twenty-eight days at biologically relevant concentrations, reaching 255.4 micromolar at a particle concentration of 1 milligram per milliliter. The hydrogels showed interconnected pores of 180 to 240 micrometers, a swelling ratio exceeding 3300 percent in the highest-loading formulation, and near-complete degradation over four weeks, with photothermal responsiveness retained even as the matrix broke down.

In cell experiments, the combination therapy showed a striking synergy against the oxidative stress that plagues diabetic tissue. When osteoblast-like MC3T3-E1 cells were challenged with hydrogen peroxide, the combined treatment of itaconate-loaded nanoparticles plus mild hyperthermia reduced intracellular reactive oxygen species to near-healthy levels, preserved mitochondrial membrane potential, and restored alkaline phosphatase activity, mineral deposition, and the expression of osteogenic genes including RUNX2 and osteocalcin to values comparable with cells grown without inflammatory challenge. Neither component alone matched this performance; mild heat by itself offered limited antioxidant protection, while itaconate alone provided only partial mitigation.

Endothelial cells benefited in parallel. In tube formation assays on Matrigel, cells exposed to the combined therapy built robust, intact tubular networks resembling those of unchallenged controls, whereas cells treated with peroxide, plain nanoparticles, or either single therapy formed fragmented vessels. The combination also upregulated the angiogenic genes Vegfa, Pdgfa, and α-SMA, addressing the vascular insufficiency that starves diabetic bone of oxygen and nutrients. Mitochondrial membrane potential in the endothelial cells followed the same protective pattern seen in the osteoblasts.

The immune effects were equally pronounced. In lipopolysaccharide-stimulated macrophages, flow cytometry showed that the combined treatment most strongly suppressed the M1 marker CD86 while raising the M2 marker CD206, and it maximized expression of the anti-inflammatory gene Arg-1 while silencing TNF-α and iNOS. In neutrophils, the therapy suppressed the formation of neutrophil extracellular traps, the web-like DNA structures that amplify diabetic inflammation and damage osteoblasts and endothelial cells. Mitochondrial membrane potential in the macrophages was likewise preserved at near-normal levels only by the combined treatment.

Transcriptomic analysis pointed to a convergent molecular target. Bioinformatic mining of public datasets from itaconate-derivative-treated neutrophils and macrophages, together with new profiling of the nanoparticle-treated cells, repeatedly highlighted the JAK1/STAT1 signaling axis and the MAPK pathway, with STAT1 and then JAK1 emerging as central hub genes. Western blotting confirmed that the combined therapy suppressed agonist-induced phosphorylation of JAK1 and STAT1 more completely than either itaconate or mild heat alone. Meanwhile, the treatment boosted macrophage secretion of fibroblast growth factor-2 to roughly two to three times the level of healthy controls, and mild heat was shown to upregulate heat shock protein 90, which stabilizes phosphorylated FGFR1 and amplifies FGF-2 signaling in target cells. Blocking HSP90 with geldanamycin attenuated this FGFR1 activation, supporting the proposed mechanism in which heat both calms inflammation and potentiates growth factor signaling.

The in vivo results tied the whole program together. In diabetic rats whose femoral defects were seeded with E. coli isolated from infected diabetic bone, the initial high-temperature treatment sharply reduced bacterial counts by day seven, and Giemsa staining found no residual bacterial colonies in the heated groups at six weeks. Micro-computed tomography revealed near-complete defect restoration in the full IMHT group, with significantly improved bone volume fraction, trabecular thickness, trabecular number, and bone mineral density compared with hydrogel implantation or antibacterial heat alone. Histology showed abundant, well-organized new bone, widespread osteocalcin expression, reduced iNOS-positive inflammatory cells, and elevated CD206-positive reparative macrophages. Major organs showed no signs of toxicity, and the 50 °C phase produced only mild local histological changes without osteonecrosis.

The authors caution that important questions remain before such a platform could approach clinical use. The long-term fate of the released nanoparticles, including their tissue retention, biodistribution, and clearance kinetics in the diabetic microenvironment, requires further quantification, and the study was conducted in a rat model over a one-month treatment window. Still, the work demonstrates a coherent design principle: rather than treating infection, inflammation, and failed regeneration as separate problems, a single material can sequence antibacterial heat, sustained immunometabolic reprogramming, and regenerative thermal activation in time, allowing each intervention to prepare the ground for the next.

Subject of Research: Immunometabolic–hyperthermia nanotherapy for regenerating infected diabetic bone defects

Article Title: Spatiotemporally coordinated immunometabolic-hyperthermia therapy for diabetic bone defect regeneration

Article References: Wang, L., Peng, X., Zheng, L., Liu, Y., Chen, L., Li, X., & Wang, Z. (2026). Spatiotemporally coordinated immunometabolic-hyperthermia therapy for diabetic bone defect regeneration. Materials Today Bio, 41, Article 103767. https://doi.org/10.1016/j.mtbio.2026.103767

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103767

Keywords: diabetic bone defects, itaconate, polydopamine nanoparticles, mild hyperthermia, macrophage polarization, JAK1/STAT1, FGF-2, HSP90, photothermal therapy, biofilm disruption, bone tissue engineering, hydrogel

Researchers synthesized the composite by using D- or L-cysteine as chiral inducers during a seed-regrowth process for gold nanorods, followed by deposition of cerium oxide nanoparticles. Circular dichroism measurements detected distinct signals for the D and L materials but none for the mixed D/L version, showing that the particles retained their handedness after coating. Electron microscopy showed that the composites retained a rod-like structure, while X-ray photoelectron spectroscopy identified coexisting Ce3+ and Ce4+ states associated with cerium oxide’s reversible redox chemistry. Coating the nanorods shifted their main optical absorption peak by 13 nanometres and slightly reduced their aspect ratio. A methoxypolyethylene glycol thiol surface layer was then added; it reversed the particles’ slightly positive zeta potential to slightly negative values and reduced hemolysis below 5% at the tested concentration of 100 micrograms per millilitre, including during near-infrared irradiation.

Light absorption made the gold component an efficient heater. Under 808 nm irradiation at 0.8 watts per square centimetre for 10 minutes, the photothermal conversion efficiencies were 52.6% for D-AuHNRs, 52.3% for L-AuHNRs and 48.4% for the mixed material. Adding cerium oxide lowered these values to 47.6%, 46.9% and 42.8%, respectively, but temperature rises still increased with particle concentration and laser power. The composites also retained their heat-generating performance through five consecutive laser on-off cycles. This physical photothermal strategy differed from reactive-oxygen-based photodynamic treatment: the nanorods killed bacteria through localized heating without relying on photogenerated reactive oxygen species that could also damage surrounding tissue. The authors described the bacterial killing mechanism as purely photothermal, distinguishing it from a photodynamic approach that generates cytotoxic reactive oxygen species.

Cerium oxide supplied the composite’s antioxidant function, which was intended to counter the excessive reactive oxygen species already present at infected wounds. In chemical assays, adding cerium oxide improved the scavenging rates of D-, L- and mixed AuHNRs. Relative to unloaded nanorods, the loaded material increased ABTS radical scavenging by 18.2% and hydroxyl-radical scavenging by 38.9% in the reported comparisons. Methylene blue degradation, tetramethylbenzidine oxidation and a salicylic acid colorimetric assay produced consistent results. The mixed D/L composite was also tested because it lacked a detectable chiral signal, providing a comparison for determining whether stereoselective interactions contributed to biological performance rather than simply reflecting the composition of the particles. CeO2 loading also reduced the nanorods’ near-infrared absorption and heat generation somewhat, showing that the antioxidant and photothermal functions were integrated rather than completely independent of one another.

Laboratory tests against Staphylococcus aureus and Escherichia coli showed that illumination was the dominant antibacterial driver. Bacterial suspensions containing the nanomaterials at 100 micrograms per millilitre were kept in darkness or irradiated for 10 minutes; colony counting, fluorescence staining, scanning electron microscopy and biofilm assays then assessed survival and structural damage. Without light, the D form was the most active against S. aureus, whereas only the D- and L-AuHNRs@CeO2 materials showed detectable activity against E. coli. Under near-infrared irradiation, every chiral configuration showed strong antibacterial activity against both organisms. Live/dead staining indicated extensive bacterial death, and crystal violet measurements showed reduced biofilm biomass. Confocal reconstructions revealed that illuminated biofilms became looser and thinner than controls, while a membrane-potential dye indicated severe depolarization after treatment with D-AuHNRs@CeO2 plus light. The same treatment also reduced the biomass of mature S. aureus and E. coli biofilms that had been cultured for 48 hours before treatment.

Microscopy and binding experiments indicated that the D configuration changed how the composite interacted with bacteria. Under illumination, treated bacteria showed collapsed membranes and leakage of intracellular contents, while nanoparticles were visibly attached to S. aureus cells. Fluorescein-labelled D-AuHNRs@CeO2 overlapped strongly with DNA staining in both bacterial species, whereas the L and mixed particles showed weaker overlap and remained largely outside the cells. Isothermal titration calorimetry gave the D composite lower dissociation constants for binding to the bacterial strains than the L and mixed configurations, consistent with stronger stereoselective association. D-AuHNRs@CeO2 also produced more heating near S. aureus after unbound particles were removed, suggesting that localization at the cell wall concentrated thermal energy. Quantification of nucleic acid and protein release showed increased leakage from both bacterial species, with especially high values after near-infrared irradiation and D-AuHNRs@CeO2 treatment. Together, these observations provided a mechanistic account for the stronger activity of the D formulation: preferential association with bacteria combined with more concentrated photothermal heating.

In mammalian cells, the D composite also performed better at reducing oxidative stress and promoting repair-related responses. After L929 fibroblasts were exposed to 2 millimolar hydrogen peroxide, DCFH-DA fluorescence and flow cytometry showed markedly lower intracellular reactive oxygen species after treatment with AuHNRs@CeO2; the D formulation produced the weakest signal. Scratch assays found greater migration by both L929 fibroblasts and human umbilical vein endothelial cells after 24 hours with D-AuHNRs@CeO2 than in the stressed controls. The D composite also increased messenger RNA expression of the antioxidant enzyme CAT and the repair-related factor TGF-β1 in L929 cells, and increased MMP1 expression in endothelial cells. These measurements showed effects on cultured-cell behaviour and gene expression under experimentally induced oxidative stress, rather than direct evidence of faster healing in patients. The investigators selected 100 micrograms per millilitre as the working concentration after hemolysis and cell-viability testing indicated that methoxypolyethylene glycol modification improved compatibility with living cells.

Cellular imaging suggested that oxidative stress influenced how the particles were taken up. Under stressed conditions, fluorescence from D-AuHNRs@CeO2 strongly colocalized with DAPI-stained cellular regions, while the L and mixed materials showed much less internalization; under normal culture conditions, signals from all three were concentrated around the cell periphery. In lipopolysaccharide-stimulated RAW264.7 macrophages, the D composite reduced expression of the M1-associated markers iNOS and IL-6 and increased the M2-associated markers CD206 and Arg-1. The authors interpreted these findings as evidence that oxidative-stress-dependent uptake enabled intracellular antioxidant activity and shifted macrophages toward a more pro-repair phenotype. The experiments were performed in cultured cell lines and did not establish how the same behavior would occur in an infected human wound. Nevertheless, the cellular results linked three measured functions: uptake of the D formulation, reduced oxidative stress and altered marker expression associated with macrophage polarization.

The strongest preclinical outcome came from infected full-thickness wounds in female BALB/c mice aged 6 to 8 weeks. Each 8-millimetre dorsal wound was inoculated with 0.1 millilitres of S. aureus at 10^7 colony-forming units per millilitre, and animals were randomly assigned to control, near-infrared, D-, L- or mixed-composite groups, with or without light. Treatments were applied on days 1 and 3, and wounds were monitored through day 12. D-AuHNRs@CeO2 plus near-infrared irradiation produced the fastest closure and the lowest bacterial counts, outperforming the non-irradiated groups and the corresponding L and mixed formulations. Colony counts were obtained from wound sites on days 3, 6, 9 and 12. A separate E. coli wound model, which included levofloxacin hydrochloride as a positive control, produced a comparable antibacterial ranking, with the D composite plus light showing the strongest effect among the tested nanoplatform groups. These results extended the antibacterial findings from culture assays to two bacterial infection models, while remaining limited to laboratory animals.

Histological examination was consistent with improved repair rather than simple suppression of infection. Control wounds retained heavy inflammatory infiltration, epidermal injury and loose connective tissue, whereas D-AuHNRs@CeO2 plus light showed a flatter wound surface, fewer inflammatory cells, nascent granulation tissue, new vessels, hair follicles and sebaceous glands. Masson’s trichrome staining showed that, by day 12, the same group had densely organized collagen fibers and a nearly continuous, thick epidermis with high keratinocyte density. Body weight changed only slightly across groups, and examinations of the heart, liver, spleen, lungs and kidneys reportedly showed no significant lesions. These observations support biocompatibility within the reported mouse experiments, but the material remains a preclinical experimental platform: the study did not test human wounds, and its findings do not demonstrate clinical benefit or establish whether the treatment would perform similarly in people.

Subject of Research: Preclinical testing of a chiral gold nanorod–cerium oxide nanoplatform for antibacterial and antioxidant wound healing.

Article Title: Synergistic photothermal and antioxidant effects of chiral gold helical nanorods @CeO 2 nanomaterials for accelerated infected wound healing

Article References: Xu, J., Li, Q., Kan, W., Liu, W., Liu, C., Liu, Q., Gao, J., Yan, K., Huang, C., & Wang, J. (2026). Synergistic photothermal and antioxidant effects of chiral gold helical nanorods @CeO2 nanomaterials for accelerated infected wound healing. Materials Today Bio, 41, Article 103754. https://doi.org/10.1016/j.mtbio.2026.103754

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103754

Keywords: chiral nanomaterials, gold nanorods, cerium oxide, photothermal therapy, infected wounds, antibacterial materials, reactive oxygen species, tissue regeneration, macrophage polarization, mouse model, Synergistic, photothermal

Macrophages are immune cells that can adopt different functional states within the tumor microenvironment. The review describes a balance between pro-inflammatory M1 macrophages and pro-tumorigenic M2 macrophages. M2 polarization can favor processes associated with tumor progression, whereas M1 polarization is linked in the reviewed evidence to inhibition of tumor growth.

Several non-coding RNAs are linked with M2 polarization in the review. miR-934, lncRNA RPPH1 and circPLCE1 are associated with M2 polarization and metastasis through signaling involving PI3K/AKT, NF-κB and STAT3. Their effects are presented as part of the molecular communication networks that connect colorectal cancer cells with tumor-associated macrophages. The review places these molecules within the broader biological context of tumor progression and metastatic behavior.

Other non-coding RNAs are associated with the M1 state. miR-195-5p and lncRNA GAS5 are described in the reviewed literature as favoring M1 polarization and suppressing tumor growth. The contrast between these molecules illustrates that non-coding RNA activity can be associated with different macrophage states and opposing effects on tumor-related processes. The mechanisms summarized in the review include exosomal transfer, competing endogenous RNA interactions and transcriptional regulation.

Transcriptional regulation provides another level at which these signals can affect cellular behavior. Together, these mechanisms form intricate communication networks between colorectal cancer cells and immune components, including tumor-associated macrophages. The review also discusses the possible translational applications of this biology.

Circulating exosomal non-coding RNAs are presented as candidate biomarkers that could improve diagnostic precision, and ncRNA-regulated macrophage polarization is identified as a possible target for immunomodulatory and precision-treatment strategies. These are research opportunities rather than established clinical benefits. Colorectal cancer remains a major global health burden, with incidence and mortality rates continuing to rise worldwide, according to the review.

The article cites a projection of 3.2 million colorectal cancer cases by 2040 and attributes this expected burden to complex interactions among genetic, environmental and lifestyle factors. The review positions ncRNA signaling within this wider disease context because these molecules may influence tumor-cell behavior, immune evasion, therapeutic resistance and the states of macrophages in the tumor microenvironment. Its central conclusion is that targeting ncRNA-regulated macrophage polarization holds promise for developing next-generation precision therapies and advancing immunomodulatory strategies in colorectal cancer.

That conclusion is a direction for research, not evidence of clinical efficacy. The review’s contribution is to assemble current knowledge about how microRNAs, long non-coding RNAs and circular RNAs relate to macrophage polarization and cancer progression, providing a framework for further investigation of these molecular connections.

Subject of Research: Non-coding RNA regulation of tumor-associated macrophage polarization in colorectal cancer

Article Title: Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis

Article References: Nami, M. T., Fattahiyan, I., Eini, P., Eramian, M., & Vanan, A. G. (2026). Macrophage polarization and non-coding RNAs in colorectal cancer progression and metastasis. Medical Oncology, 43(11), Article 350. https://doi.org/10.1007/s12032-026-03482-5

Image Credits: AI Generated

DOI: 10.1007/s12032-026-03482-5

Keywords: colorectal cancer, non-coding RNAs, tumor-associated macrophages, macrophage polarization, microRNAs, long non-coding RNAs, circular RNAs, cancer metastasis, tumor microenvironment, exosomal biomarkers, Macrophage, polarization

The investigation used two publicly available gene-expression datasets from the Gene Expression Omnibus. GSE26051 served as the training cohort, while differential-expression results from GSE180836 contributed to candidate-gene discovery and screening. Because GSE180836 informed candidate selection, it was not used as an independent validation cohort. The selected biomarkers were instead assessed by reverse-transcription quantitative PCR, or RT-qPCR, in a separate clinical cohort containing 30 participants. This design meant that the principal laboratory confirmation came from clinical samples rather than from a second independent analysis of the public transcriptomic datasets.

To identify differentially expressed genes associated with the macrophage polarization-related transcriptional signature, the researchers combined differential-expression analysis with weighted gene co-expression network analysis, known as WGCNA. Three machine-learning algorithms were then applied to screen candidate biomarkers: least absolute shrinkage and selection operator, support vector machine-based recursive feature elimination, and the Boruta algorithm. The analysis selected PTCHD1, NEURL1, and ST8SIA5, all of which were significantly downregulated in the training cohort GSE26051.

Clinical testing supported two of the three candidates more clearly than the third. PTCHD1 and NEURL1 were each significantly downregulated in tendinopathy samples relative to controls in the cohort of 30, with P values below 0.01 for both comparisons. ST8SIA5 also exhibited a downward trend, but the difference did not reach statistical significance, with P = 0.074. On this evidence, PTCHD1 and NEURL1 were the more strongly supported markers associated with tendinopathy, while ST8SIA5 remained a candidate showing a consistent but inconclusive expression pattern.

The researchers also constructed a diagnostic nomogram from the selected biomarkers and evaluated it using receiver operating characteristic and calibration analyses. The model achieved an area under the ROC curve above 0.7 and showed good calibration. These results indicate that the model discriminated between the groups represented in the study, but the reported evidence does not establish its diagnostic performance in larger or more diverse populations. The distinction is particularly important because the public dataset GSE180836 contributed to candidate discovery rather than serving as an independent validation set, while the clinical cohort used for RT-qPCR confirmation included only 30 participants.

Functional enrichment and gene-set analyses associated the biomarker-related network with pathways including PI3K–Akt signaling and extracellular matrix–receptor interaction. These are computational associations within the studied expression data, not evidence that PTCHD1 or NEURL1 directly controls macrophage polarization or that either gene is a therapeutic target. Similarly, a drug–gene interaction analysis identified 16 potential therapeutic compounds, but the source reports network-level candidates rather than experimental tests of treatment effects. The study’s strongest supported finding is therefore the clinical association of reduced PTCHD1 and NEURL1 expression with tendinopathy, alongside a gene-based model that showed discrimination above 0.7 AUC in the available validation material.

Subject of Research: Macrophage-associated transcriptional biomarkers for tendinopathy

Article Title: Identification of genes associated with a macrophage polarization-related transcriptional signature as biomarkers for tendinopathy based on bioinformatics analysis

Article References: Ren, L., He, C., & Qin, Y. (2026). Identification of genes associated with a macrophage polarization-related transcriptional signature as biomarkers for tendinopathy based on bioinformatics analysis. Scientific Reports. https://doi.org/10.1038/s41598-026-75576-z

Image Credits: AI Generated

DOI: 10.1038/s41598-026-75576-z

Keywords: tendinopathy, macrophage polarization, PTCHD1, NEURL1, ST8SIA5, gene biomarkers, RT-qPCR, WGCNA, machine learning, diagnostic nomogram, Identification, genes

Across several strategies, compensation between myeloid lineages, selective resistance and damage to beneficial immune functions repeatedly interrupt otherwise plausible therapeutic effects. The review, published on October 20, 2026, in Frontiers in Pharmacology, examines macrophages, monocytes, neutrophils, myeloid-derived suppressor cells and dendritic cells that jointly regulate immune exclusion, T-cell dysfunction, angiogenesis, stromal remodeling and resistance to immune checkpoint blockade. These populations are not interchangeable drug targets.

Human tumor-associated macrophages can simultaneously express inflammatory, scavenging, angiogenic, lipid-handling, matrix-remodeling and antigen-presentation programs, making the familiar M1-versus-M2 classification unsuitable as a pharmacodynamic endpoint. Suppressive-cell phenotypes are also difficult to identify reliably because polymorphonuclear myeloid-derived suppressor cells overlap with neutrophils, while monocytic populations overlap with conventional monocytes. Studies should therefore predefine the population being targeted, report absolute cell abundance, distinguish depletion from redistribution and use functional or spatial evidence alongside marker expression.

MICAT extends an established pharmacological audit trail by inserting an ecosystem-propagation step between modification of a myeloid cell and a clinical outcome. Each level receives a score from zero to two: zero for absent or negative evidence, one for partial or indirect evidence, and two for a demonstrated criterion. Level 1 requires direct tumor exposure or receptor engagement linked to proximal pharmacodynamic effects.

Level 2 requires a prespecified lineage-specific change in cell state or function, with absolute abundance accounted for. Level 3 demands concordant evidence in at least two downstream domains, such as antigen-presenting-cell function, adaptive-effector activity, clonal change or spatial organization. Level 4 requires benefit attributable to the experimental agent in a component-controlled randomized comparison.

The eight-point total measures completeness of causal evidence, not drug potency, commercial promise or probability of future success. CSF1R inhibition illustrates the difference between target activity and immune conversion. In the randomized phase III ENLIVEN trial for advanced tenosynovial giant-cell tumor, pexidartinib produced a week-25 response in 39% of patients, compared with none receiving placebo, establishing randomized benefit in a strongly CSF1-dependent neoplasm.

That result does not prove immune conversion in carcinomas because the trial did not demonstrate conversion of a myeloid state and downstream ecosystem propagation. In the phase I MEDIPLEX trial in colorectal and pancreatic cancers, pexidartinib plus durvalumab produced systemic CSF1R pharmacodynamic effects, but only one of 47 patients achieved a partial response, in MSI-high colorectal cancer. Pexidartinib’s additional inhibition of FLT3 and c-KIT impaired dendritic-cell differentiation, reduced dendritic-cell subsets and weakened interferon-lambda-related function, showing how a nominally macrophage-directed drug can damage the antigen-presenting bridge required for checkpoint therapy.

Antibody programs targeting CSF1R have similarly separated target engagement from clinical benefit. Emactuzumab plus atezolizumab reduced CSF1R-dependent populations and produced objective response rates of 5.6% to 12.5% across cohorts, without evidence that checkpoint resistance had been reversed. AMG 820 plus pembrolizumab increased CSF1 and IL-34, reduced selected circulating monocytes and raised several intratumoral immune markers, yet immune-related partial responses occurred in only 3% of 116 patients.

Toxicities include edema, transaminase elevations, fatigue and rash, while pexidartinib also carries risks of mixed or cholestatic hepatotoxicity. The review does not invalidate CSF1R as a target, but narrows the conditions for success: carcinoma trials should select a defined suppressive macrophage state, document its disappearance in tumor tissue, verify preservation of conventional type 1 and type 2 dendritic cells, and compare continuous with pulsatile schedules. Recruitment blockade is vulnerable to biological redundancy.

CCR2 and CCR5 direct monocyte trafficking, while CXCR1 and CXCR2 recruit neutrophils and polymorphonuclear suppressor-like cells. In paired samples from pancreatic ductal adenocarcinoma, CCR2 inhibition reduced monocyte and macrophage influx but allowed CXCR2-positive neutrophils to substitute; mouse experiments showed that blocking either population could expand the alternative one. Clinical results have been inconsistent.

In first-line pancreatic cancer, BMS-813160 with chemotherapy and nivolumab produced a 37% response rate, compared with 26% for BMS-813160 plus chemotherapy and 28% for chemotherapy alone; in second-line colorectal cancer, neither experimental regimen clearly improved activity over FOLFIRI. Earlier CCR2 blockade produced encouraging signals in small, nonrandomized studies but not convincing added efficacy in metastatic disease, and it was associated with pulmonary toxicity in 24% of one trial’s patients, including grade 4 hypoxia. Navarixin with pembrolizumab showed little activity across prostate cancer, microsatellite-stable colorectal cancer and non-small-cell lung cancer.

PI3Kγ inhibition offers a different mechanism because it seeks to reprogram myeloid cells without necessarily depleting them. In the single-arm phase II MARIO-3 trial of eganelisib, atezolizumab and nab-paclitaxel in first-line metastatic triple-negative breast cancer, paired biopsies from 29 patients showed increased MHC class I and II and CXCL9/CXCL10 programs, reduced SPP1, metalloprotease and extracellular-matrix programs, and an increased CXCL9-to-SPP1 balance. The digital-spatial and multiplex-imaging analyses used smaller subsets of 12 and 11 patients, respectively.

These regimen-level changes were consistent with myeloid-state conversion and ecosystem propagation, but the trial did not demonstrate agent-specific intratumoral PI3Kγ engagement, and both chemotherapy and checkpoint blockade can alter the same readouts. The decisive test proposed by the review is a randomized comparison using the same chemotherapy and checkpoint backbone with or without eganelisib, direct tumor engagement and a conversion score locked before unblinding. CD40 agonism attempts to license dendritic cells, restore co-stimulation and cross-priming, and reshape macrophage and stromal interactions, but receptor clustering, epitope, valency, tumor anchoring, dose and schedule can make the agents behave differently.

In the randomized phase II PRINCE trial, neither sotigalimab-containing arm met its prespecified one-year overall-survival benchmark, although exploratory CD4, dendritic-cell and antigen-presenting-cell features were associated with benefit. Single-arm studies of mitazalimab reported encouraging response and survival estimates alongside dynamic circulating immune changes, but could not isolate its contribution. Tumor-localized agonists made the distinction between delivery and efficacy especially clear: MP0317 and RO7300490 achieved tumor localization and partial CD40 pathway activation, yet objective responses were absent or exceptional.

The review places high priority on sequence-aware studies in resectable pancreatic ductal adenocarcinoma, where surgery can provide tissue for measuring antigen-presenting-cell activation, stromal remodeling and T-cell effects. CD47–SIRPα blockade seeks to release macrophage inhibition of phagocytosis, but CD47 is widely expressed on normal cells, creating anemia, thrombocytopenia, hemagglutination, transfusion interference and infusion-reaction risks. In first-line head and neck squamous-cell carcinoma, adding magrolimab to pembrolizumab and chemotherapy did not improve progression-free survival and increased grade 3–4 adverse events.

ELEVATE CRC was also stopped early: median progression-free survival was 6.2 months with magrolimab plus bevacizumab-FOLFIRI and 6.7 months with bevacizumab-FOLFIRI alone, while grade 3 or higher treatment-emergent adverse events occurred in 72.7% and 52.4% of the respective groups. An exploratory conference report from ASPEN-06 suggested that fresh-biopsy confirmation of retained HER2 might enrich activity for evorpacept paired with HER2-directed therapy, but the historical comparison was nonsignificant and the subgroup analysis exploratory. Preservation of the tumor antigen used for opsonization is therefore a candidate biomarker requiring prospective confirmation.

Emerging targets and engineered platforms remain earlier in development. Early Clever-1, TREM2 and LILRB2 programs established dose feasibility and initial safety profiles, but peripheral occupancy, exploratory interferon signatures and small paired-tissue subsets did not establish intratumoral target conversion. In vivo lipid-nanoparticle macrophage programming, bispecific myeloid engagers and artificial-intelligence-assisted spatial scoring remain subject to the same evidentiary requirements as conventional drugs.

The review’s practical rule is strict: stop dose escalation when tumor engagement is saturated but myeloid conversion is absent, redesign a combination when conversion fails to propagate, and withhold claims of a validated immune switch until randomized benefit completes the causal chain.

Subject of Research: Evidence standards for pharmacological reprogramming of suppressive myeloid cells in solid tumors

Article Title: Pharmacological reprogramming of myeloid suppression in solid tumors: mechanisms, evidence standards for immune conversion, and biomarker-informed combinations

Article References: Maletin, N., Denda, N., Paut Kusturica, M., Rašković, A., Babović, S., & Golušin, Z. (2026). Pharmacological reprogramming of myeloid suppression in solid tumors: mechanisms, evidence standards for immune conversion, and biomarker-informed combinations. Frontiers in Pharmacology, 17, Article 1986842. https://doi.org/10.3389/fphar.2026.1986842

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1986842

Keywords: myeloid immune conversion, solid tumors, tumor-associated macrophages, immune checkpoint blockade, CSF1R inhibition, PI3Kγ inhibition, CD40 agonism, CD47 blockade, pharmacodynamic biomarkers, MICAT, Pharmacological, reprogramming

The scale of the problem is staggering. An estimated 2.21 in every 1,000 people worldwide live with chronic wounds, which typically persist for twelve to thirteen months and recur in as many as 60 to 70 percent of patients. Diabetic ulcers are among the worst offenders, and their origins lie in a fundamental breakdown of coordination. Normal wound healing unfolds in four precisely choreographed phases—hemostasis, inflammation, proliferation, and remodeling—and when any phase falls out of step, the entire repair program can stall. The new review, led by Keerthan Nayak and colleagues at Manipal Academy of Higher Education, maps how autophagy governs this choreography and where it goes wrong in diabetic and non-healing wounds.

At the molecular level, autophagy is a lysosome-dependent degradation pathway conserved across virtually all eukaryotic life. In its best-studied form, macroautophagy, a membrane structure called a phagophore expands to engulf cytoplasmic cargo, sealing it inside a double-membrane vesicle known as an autophagosome. This vesicle then fuses with a lysosome to form an autolysosome, where hydrolytic enzymes dismantle the contents. The process runs through a defined molecular assembly line: the ULK1 complex initiates the cascade, a class III PI3K complex containing Beclin-1 generates phosphatidylinositol-3-phosphate at the assembly site, and the ATG5-ATG12-ATG16L1 conjugation system drives lipidation of the protein LC3, expanding the autophagosome membrane. Final fusion with lysosomes depends on the small GTPase RAB7 and SNARE proteins.

What makes autophagy so relevant to wounds is the way it is switched on and off. Under nutrient-rich conditions, the pathway is suppressed by mTORC1, the mammalian target of rapamycin complex 1, acting through the PI3K-AKT signaling axis. When cells face the opposite conditions—hypoxia, oxidative stress, ATP depletion, nutrient scarcity, precisely the conditions inside an open wound—AMP-activated protein kinase, or AMPK, takes command. AMPK inhibits mTORC1 and directly phosphorylates ULK1 and Beclin-1 to ignite autophagy. In other words, the wound microenvironment is almost purpose-built to activate the very pathway that helps cells survive it.

The review details autophagy’s role in each phase of healing. During inflammation, pattern recognition receptors such as toll-like receptors and the NOD-like receptors NOD1 and NOD2 stimulate autophagy after sensing microbial invasion, promoting the engulfment and destruction of pathogens in a process called xenophagy. Autophagy also shapes the inflammatory signal itself: in macrophages, secretory autophagy promotes the release of the inflammatory messengers IL-1β and HMGB1, while the pathway helps steer macrophages from their pro-inflammatory M1 state toward the pro-repair M2 state. That switch, however, is context-dependent. In diabetic settings, advanced glycation end-products can drive autophagy toward harmful M1 polarization via IRF8, actually impairing wound closure.

In the proliferative phase, autophagy keeps the repair machinery moving. Hypoxia in the wound bed raises reactive oxygen species, which activate p38 and JNK MAPK signaling and trigger BNIP3-mediated autophagy in keratinocytes, facilitating their migration across the wound and accelerating re-epithelialization. Experiments comparing keratinocytes lacking the essential autophagy gene Atg7 with normal cells showed that autophagy-deficient cells are far more vulnerable to oxidative stress, accumulating DNA damage and slipping into premature senescence. Hypoxia-driven autophagy also preserves endothelial cell function and promotes angiogenesis, ensuring new blood vessels reach the healing tissue. During the final remodeling stage, autophagy regulates fibroblast differentiation into myofibroblasts, collagen maturation, and even the clearance of cells that would otherwise drive hypertrophic scarring.

The translational implications are where the review becomes genuinely provocative, because a growing arsenal of drugs and materials can now manipulate the pathway. Rapamycin, the classic mTORC1 inhibitor, accelerates healing and reduces scarring in rodent models, and mesenchymal stem cells primed with rapamycin release exosomes that enhance diabetic wound repair by promoting VEGF-driven angiogenesis and shifting macrophages toward the M2 phenotype. Metformin, the world’s most widely prescribed diabetes drug, activates AMPK; topical metformin gels raised markers of autophagy such as LC3B and Beclin-1 and improved collagen deposition and re-epithelialization in diabetic rats. Plant-derived compounds add to the list: resveratrol protects diabetic wounds by modulating PI3K/AKT/Nrf2 signaling and blocking ferroptosis, green tea’s epigallocatechin gallate restores impaired autophagic flux in high-glucose-treated keratinocytes through AMPK/ULK1, and curcumin’s protective effects in stressed fibroblasts vanish entirely when autophagy is blocked.

Biomaterials are emerging as perhaps the most elegant delivery solution. Zwitterionic sulfobetaine methacrylate hydrogels promote near-complete skin regeneration by dampening PI3K/AKT/mTOR signaling, while thermosensitive injectable hydrogels pairing zinc with metformin raised LC3 expression at the wound site and sped full-thickness skin repair. Electrospun chitosan nanofibers loaded with the antioxidant dihydromyricetin boosted autophagy-associated proteins including LC3-II, ATG5, and ATG7 while suppressing inflammation. Even strategies that inhibit autophagy have a place: PLGA microspheres releasing platelet-derived growth factor can suppress excessive autophagy in endothelial cells and fibroblasts, unleashing angiogenesis and granulation tissue formation. The common thread is localization—delivering the right modulator to the right cells at the right time, with minimal systemic exposure.

Yet the authors are candid about the obstacles standing between the laboratory and the clinic. Most autophagy-modulating compounds suffer from poor solubility, limited skin penetration, instability, and off-target effects that ripple through inflammation, cell proliferation, and angiogenesis. Rapamycin’s immunosuppression and metabolic side effects, for instance, mean even topical use demands caution. More fundamentally, much of the preclinical evidence rests on static marker readouts such as LC3 puncta or Beclin-1 levels, which cannot distinguish genuine autophagic flux from a blocked degradation step. The review calls for rigorous flux assays, including bafilomycin A1 inhibition and tandem fluorescent LC3 reporters, alongside well-controlled human trials that remain scarce. There are also open biological questions: whether chronic wounds fail at autophagy initiation or lysosomal clearance, which cell types to target at each phase, and whether selective pathways such as mitophagy and ER-phagy outperform general autophagy manipulation.

The bigger picture emerging from this synthesis is that autophagy is neither uniformly good nor bad for healing—it is a dial that must be tuned. Too little autophagy leaves cells unable to adapt to the hostile wound environment; too much, particularly in chronic diabetic wounds, can feed pathological inflammation and fibrosis. The authors argue the therapeutic goal should be restoring normal autophagic flux in the correct cells, wound type, and healing stage, ideally using smart biomaterials capable of controlled, sequential drug release. If that precision can be achieved, the humble cellular recycling system may finally deliver what millions of patients with non-healing wounds have been waiting for: a way to turn stalled, inflamed wound beds back into regenerating tissue.

Subject of Research: The role of autophagy in cutaneous wound healing and therapeutic strategies targeting it

Article Title: Rewiring autophagy to target cutaneous wound healing: investigation of molecular mechanisms to therapeutic interventions

Article References: Nayak, K., Banerjee, I., Nazerulla, F., Valame, A., Paul, M. K., Bhutia, S. K., Basu, D., & Mukhopadhyay, S. (2026). Rewiring autophagy to target cutaneous wound healing: investigation of molecular mechanisms to therapeutic interventions. Molecular Biology Reports, 53(1), Article 1751. https://doi.org/10.1007/s11033-026-12938-w

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12938-w

Keywords: autophagy, wound healing, chronic wounds, diabetic ulcers, mTOR, AMPK, macrophage polarization, keratinocytes, angiogenesis, phytochemicals, biomaterials, exosomes

PRKDC, formally known as the protein kinase, DNA-activated, catalytic polypeptide, encodes the catalytic subunit of the DNA-dependent protein kinase, a molecular machine central to non-homologous end joining, the cellular pathway that stitches double-strand DNA breaks back together. Because of this role, PRKDC has traditionally been studied in the context of genome stability, radiation sensitivity, and lymphocyte development. Yet accumulating evidence has implicated PRKDC in tumor progression across several cancer types, and the new study set out to determine whether the gene also shapes the tumor microenvironment in hepatocellular carcinoma, where tumor-associated macrophages are abundant and tend to adopt an immunosuppressive phenotype.

To test this, the researchers engineered mouse Hepa1-6 liver cancer cells that overexpressed PRKDC and implanted them into mice using both subcutaneous and orthotopic models, the latter recreating tumors within the liver itself. The results were clear: PRKDC overexpression enhanced malignant behaviors in vitro, including proliferation and other hallmarks of aggressive cancer, and accelerated tumor growth in vivo. This established PRKDC not merely as a passive correlate of tumor aggressiveness but as a driver of malignant phenotypes in hepatocellular carcinoma.

The next question was how a DNA repair kinase could exert such broad influence over tumor behavior. Using Olink proteomics, RNA sequencing, quantitative PCR, ELISA, and immunohistochemistry, the team found that PRKDC upregulated CSF1, also known as colony-stimulating factor 1, a secreted cytokine that acts as a key growth and differentiation factor for macrophages. Database analyses further supported CSF1R, the CSF1 receptor, as the primary receptor through which CSF1 signals, and single-cell analysis showed that CSF1R was enriched specifically in tumor-associated macrophages within the tumor microenvironment.

This finding reframed the biology of the tumor microenvironment in hepatocellular carcinoma. Rather than acting solely through intrinsic cancer cell pathways, PRKDC appeared to function as a signaling hub that recruits and reprograms immune cells. By secreting CSF1, PRKDC-overexpressing tumor cells could engage CSF1R on macrophages, nudging them toward an M2-like polarization state. M2 macrophages are known for promoting tissue repair and wound healing, but in the context of cancer they suppress antitumor immunity, support angiogenesis, and facilitate metastasis, making them one of the most treacherous components of the tumor microenvironment.

To validate this mechanism, the researchers performed CSF1R knockdown in mouse RAW264.7 macrophages, which reduced the expression of M2 markers induced by IL-4, a cytokine that normally drives M2 polarization. This demonstrated that CSF1R signaling is required for the M2 program in these macrophages. Immunohistochemistry, co-culture experiments, and flow cytometry then showed increased expression of M2-like tumor-associated macrophage markers in tumors overexpressing PRKDC, confirming that the PRKDC-CSF1 axis reshapes macrophage identity within the tumor microenvironment in living systems, not just in isolated cells.

Perhaps the most striking finding came from macrophage phagocytosis assays. Macrophages are professional phagocytes, capable of engulfing and digesting abnormal cells, including cancer cells that display eat-me signals. The study found that PRKDC-mediated CSF1 upregulation was associated with increased resistance of hepatocellular carcinoma cells to macrophage phagocytosis. In other words, by pushing macrophages toward an M2-like state, PRKDC-overexpressing tumor cells effectively disarmed the very immune cells that should be eliminating them, converting macrophages from attackers into supporters of tumor growth.

Collectively, the study proposes a coherent model: PRKDC promotes hepatocellular carcinoma progression by upregulating CSF1, activating the CSF1/CSF1R pathway, and inducing M2-like polarization of tumor-associated macrophages, thereby impairing phagocytosis and contributing to immune evasion. This PRKDC-CSF1/CSF1R-tumor-associated macrophage axis may represent a potential therapeutic target in hepatocellular carcinoma, a disease where immune checkpoint inhibitors have shown benefit but where many patients still fail to respond, partly because of the immunosuppressive tumor microenvironment.

The findings carry particular weight because hepatocellular carcinoma is highly lethal and immune evasion is a major barrier to treatment efficacy. Tumor-associated macrophages are abundant in hepatocellular carcinoma and tend to polarize toward an M2-like phenotype, contributing to immune evasion and limiting the impact of immunotherapy. By identifying PRKDC as an upstream regulator of this process, the study adds a new layer to the understanding of how liver tumors manipulate their surroundings and suggests that targeting the PRKDC-CSF1/CSF1R pathway could complement existing immunotherapeutic strategies.

While the research was conducted in mouse models and cell lines, and further work will be needed to confirm the mechanism in human tumors and patients, the study offers a compelling example of how a gene with a well-established role in DNA repair can moonlight as a regulator of immune privilege in cancer. As the field of tumor immunology continues to uncover the complex crosstalk between cancer cells and their microenvironment, studies like this one highlight the importance of looking beyond intrinsic cancer cell pathways to understand how tumors co-opt the immune system for their own survival.

Subject of Research: PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization

Article Title: PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization

Article References: Wang, Y., Pang, W., Lu, X., Wu, H., Li, M., Pan, M., Tan, J., He, J., Luo, Y., Lin, H., Li, M., & Yu, Y. (2026). PRKDC orchestrates immune evasion in hepatocellular carcinoma through CSF1/CSF1R-mediated M2 macrophage polarization. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04600-y

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04600-y

Keywords: hepatocellular carcinoma, PRKDC, CSF1, CSF1R, macrophage polarization, tumor microenvironment, immune evasion, phagocytosis, liver cancer, cancer immunology, orchestrates, immune

The biological rationale for electrical stimulation rests on a phenomenon that has fascinated scientists since the nineteenth century. The German physiologist Emil Du Bois-Reymond first recorded faint bioelectric currents at injured skin in the 1800s, and in the 1980s researchers Barker and colleagues measured voltage differences of thirty to one hundred millivolts across hairless guinea pig skin, proposing what became known as the skin battery hypothesis. The modern explanation involves the transepithelial potential, a voltage generated by the polarized distribution of ion channels and pumps in epithelial cell membranes, together with active ion transport by Na+/K+-ATPase. Intact skin typically sits ten to sixty millivolts negative relative to underlying tissue. When the epithelial barrier is broken, this potential is locally short-circuited, and ions flow from surrounding healthy tissue toward the wound center, creating a lateral direct-current electric field of roughly forty to two hundred millivolts per millimeter directed from the wound periphery to its core.

That endogenous field is not a passive curiosity; it is an active steering mechanism for repair. In vivo imaging by Nuccitelli and colleagues confirmed that a mouse skin wound edge carries a field of about 177 millivolts per millimeter, sustained at peak intensity for roughly three days before declining as re-epithelialization proceeds. Different cell types respond with striking specificity: neutrophils and keratinocytes migrate toward the cathode, while fibroblasts and macrophages move toward the anode. Even endothelial cells split by origin, with microvascular cells migrating cathodally and macrovascular cells anodally. Gene knockout experiments identified phosphatidylinositol-3-OH kinase-gamma and PTEN as master regulators of this electrotactic behavior, with loss of the kinase abolishing directional migration and loss of the phosphatase amplifying it. Crucially, in three independent diabetic animal models, researchers found that wounds in diabetic tissue generate significantly weaker electric signals than healthy tissue, offering a concrete biophysical explanation for why chronic wounds stall in the inflammatory phase.

The clinical evidence for harnessing this biology has grown steadily. A recent meta-analysis of ten randomized controlled trials covering 451 patients with diabetic ulcers found that electrical stimulation with electrodes placed on or around the wound significantly improved healing rates compared with standard care alone, with a relative risk of 1.45. Yet conventional electrotherapy equipment remains tethered to external power supplies, demands complicated procedures, and restricts patient mobility—limitations that have kept electroceutical wound care from widespread adoption. The review’s central argument is that a new generation of materials can dissolve these barriers by embedding the electrical function directly into the dressing itself.

The first of the three material categories, conductive hydrogels, exploits the fact that hydrogels already make ideal wound dressings: they hold large amounts of moisture, are highly biocompatible, and mechanically mimic soft tissue. By weaving electroactive components into the hydrogel network—conductive polymers such as polyaniline, polypyrrole and PEDOT:PSS, carbon nanomaterials including graphene, carbon nanotubes and the two-dimensional MXenes, or metal nanoparticles—researchers create flexible electrodes that conform closely to irregular wound surfaces. This conformal contact lowers the impedance at the tissue interface, allowing safe stimulation at comparatively low voltages and avoiding the localized current densities that poor contact with rigid metal electrodes can produce. Most current designs target conductivity between ten to the minus three and ten to the minus one siemens per centimeter, a range chosen to approximate the electrical properties of hydrated dermal tissue. In animal studies, a three-dimensional conductive hydrogel scaffold seeded with dermal fibroblasts and paired with external stimulation produced the fastest wound contraction in full-thickness rat wounds, with higher vessel density and collagen accumulation than either component alone. A MXene-based nanocomposite hydrogel combined with antimicrobial peptides and suitable stimulation accelerated healing and improved final closure relative to both untreated controls and MXene-free hydrogels.

The review is candid, however, about a fundamental weakness in the most fashionable of these additives. MXenes, particularly the archetype Ti3C2Tx, oxidize readily in aqueous, oxygen-rich environments: within days, the transition metal surface converts to oxides such as TiO2 and conductivity deteriorates sharply. Surface passivation coatings, antioxidant agents, and protective hydrogel matrices are under investigation, but these strategies have been validated mostly in vitro, and the retention of MXene conductivity under the enzymatic and oxidative conditions of a real wound over the full healing period has not been systematically demonstrated. Hydrogels also swell and degrade in the moist wound bed, steadily eroding both conductivity and structure, and the long-term toxicology of conductive fillers and their degradation byproducts remains incomplete.

The second category, self-powered materials, tackles the power problem head-on by converting ambient mechanical energy into therapeutic fields. Piezoelectric polymers such as polyvinylidene fluoride and its copolymers generate charge in response to deformation, while triboelectric nanogenerators harvest electricity from contact and separation between surfaces—so ordinary movements like joint bending, muscle stretching, and the expansion of the chest during breathing become the power source. One team fabricated a flexible piezoelectric film from a P(VDF-TrFE) copolymer modified with tetrabutylammonium chloride, which boosted output voltage roughly 5.3-fold; placed on rat skin wounds, the film generated fields spontaneously from body motion and achieved near-complete closure by day seven. An ionic triboelectric nanogenerator patch converted movement into power for demand-coupled delivery of therapeutic zinc ions in diabetic mice, showing antibacterial effects, enhanced angiogenesis, and accelerated healing. But the review highlights a sobering quantitative mismatch: triboelectric devices typically produce open-circuit voltages in the tens to hundreds of volts, while the fields that optimally guide cell migration correspond to only 0.04 to 1 volt across a typical wound distance. Raw outputs are fifty to one thousand times higher than the biological sweet spot, pulsatile rather than steady, and randomly timed—meaning that power management circuits capable of conditioning harvested energy into a therapeutically relevant waveform are not an optional extra but an essential design element.

The third category, integrated multifunctional systems, reflects the recognition that chronic wounds present multiple simultaneous pathologies—infection, excess exudate, persistent inflammation, hypoxia, and growth factor depletion—that no single function can address. One 2023 study coupled negative pressure wound therapy with a triboelectric generator, converting the rhythmic mechanical deformations of the therapy itself into a safe supplementary electric field while simultaneously providing drainage and swelling relief. A biomimetic neuro-immuno-regulatory platform assembled from MXene nanosheets, decellularized adipose tissue and basic fibroblast growth factor integrated exudate control, conductivity, antioxidant activity, controlled delivery and immunomodulation in one structure, driving macrophages from the pro-inflammatory M1 state toward the reparative M2 phenotype in diabetic wounds. An asymmetric nanofibrous scaffold with hydrophilic and hydrophobic layers moved exudate directionally while activating copper-zinc galvanic pairs to generate a continuous microcurrent of about 465 millivolts that triggered curcumin release. The frontier now visible is the closed-loop smart bandage: a 2025 Nature Communications paper described a self-powered, breathable electronic bandage providing continuous wound monitoring with responsive drug delivery, tested clinically in patients aged eighteen to ninety-five, while a separate wireless system called a-Heal uses wearable imaging and machine learning to assess healing stage and deliver electrical stimulation or medication accordingly.

Underlying all three categories is a mechanistic story that the review assembles with unusual quantitative care. Electric fields establish directional signals through the PI3K-gamma/PTEN polarity pathway, with calcium influx and the mechanosensitive channel Piezo1 feeding into PI3K/Akt and MAPK/ERK cascades. In the inflammatory phase, fields as weak as five millivolts per millimeter direct macrophage migration and enhance phagocytosis; continuous three-day exposure reduced the local M1-to-M2 ratio by 30.6 percent in a murine model, accompanied by falling TNF-alpha and IL-1beta and rising IL-10. In the proliferative phase, keratinocytes migrate cathodally in coordinated sheets above roughly fifty millivolts per millimeter, fibroblasts differentiate into contractile myofibroblasts through TGF-beta1/ERK/NF-kappaB signaling at fifty to one hundred millivolts per millimeter, and endothelial cells form tubular structures through VEGF receptor signaling at seventy-five to one hundred millivolts per millimeter. In remodeling, pulsed fields activate matrix metalloproteinases while suppressing TGF-beta1, limiting excessive collagen accumulation and scar formation—one wearable electret patch suppressed type I collagen expression by ninety percent in vitro. Electric fields also disrupt bacterial biofilms directly: in an ex vivo human skin model, stimulation reduced viable Pseudomonas aeruginosa by more than sixty percent, and a wireless electroceutical dressing using a silver-zinc redox couple prevented and disrupted mixed-species biofilms over fifty-six days in a porcine model.

The review closes with a clear-eyed assessment of what stands between these laboratory successes and routine clinical use. There is no single optimal stimulation parameter set: field strengths in the literature span forty to three hundred millivolts per millimeter, durations range from minutes to days, and waveforms span direct current, pulsed, and alternating current, with each cell type showing distinct sensitivity thresholds. Long-term durability in the moist wound environment, comprehensive biosafety evaluation of degradation products, manufacturing scalability, sterilization compatibility, and regulatory pathways remain largely unexplored. The authors’ proposed destination is a closed-loop intelligent repair system that senses wound conditions, decides on a therapeutic response, and adjusts stimulation in real time—beginning with simple pH- or temperature-triggered feedback and evolving toward machine-learning-driven, multi-modal platforms that coordinate electric fields with mechanical forces and spatiotemporally controlled biochemical cues. If that vision matures, the humble wound dressing could evolve from a passive covering into an adaptive bioelectronic interface that reads the wound’s own electrical language and speaks back to it.

Subject of Research: Electroactive materials for electrical stimulation of skin wound healing

Article Title: Advances in electroactive materials-based strategies for promoting skin wound healing

Article References: Ge, H., Ren, X., & Lei, Z. (2026). Advances in electroactive materials-based strategies for promoting skin wound healing. Frontiers in Medical Technology, 8, Article 1919503. https://doi.org/10.3389/fmedt.2026.1919503

Image Credits: AI Generated

DOI: 10.3389/fmedt.2026.1919503

Keywords: wound healing, electrical stimulation, conductive hydrogels, self-powered materials, triboelectric nanogenerators, piezoelectric materials, MXene, endogenous electric fields, chronic wounds, smart dressings, macrophage polarization, closed-loop systems