A major bottleneck in radio-immunotherapy is the inability to precisely couple the localized stimulus of radiotherapy (RT) with the systemic action of immunotherapeutics. To bridge this gap, we developed a chemically engineered RT-ignited nanoplatform that productively harnesses the biochemical consequences of RT to precisely activate immunotherapy locally, thereby amplifying its benefits while minimizing systemic exposure. The platform co-delivers a hydrogen sulfide (H₂S)-responsive prodrug of toll-like Toll-like receptor 7/8 (TLR7/8) agonist imiquimod (IMQ) using a reactive oxygen species (ROS)-sensitive, targeted nanocarrier. RT ignites a biochemical sequence: ROS bursts disassemble the carrier, and the subsequent H₂S upregulation cleaves the prodrug, ensuring tumor-localized drug release. This RT-primed, sequentially activated therapy profoundly enhances antitumor immunity by inducing immunogenic cell death (ICD), activating antigen-presenting cells (APCs), and overcoming systemic immunosuppression, culminating in durable tumor regression and immunological memory. This study highlights a chemistry-driven approach to spatially and temporally confine immune activation to the tumor site, effectively broadening the therapeutic window and transforming RT-induced biochemical changes into a precise trigger for systemic immunity.

Background: Psoriasis is a chronic inflammatory skin disease due to genetic susceptibility and multiple environmental factors. Transient receptor potential vanilloid 4 (TRPV4) is a calcium channel extensively expressed throughout the body with multiple functions. However, the role of TRPV4 in imiquimod (IMQ)-induced -psoriasis progression remains unclear although it is ubiquitously expressed in skin tissues and participates in cutaneous mechano- and thermo-sensation. Methods: Both in vivo and in vitro studies were performed in murine skin tissue and isolated cells. TRPV4 expression, autophagy, and Akt/mTOR phosphorylation were assessed by Western blot and reactive oxygen species (ROS) generation was examined by MitoSOX staining. Cytokine levels were measured by ELISA and cell proliferation was determined by CCK staining. The severity of psoriasis was also checked by psoriasis severity index (PSI), scale and thickness scoring and microscopic observations. Results: IMQ-induced psoriasis was remarkably attenuated in TRPV4 knockout mice compared with their wild-type counterparts, accompanied by reduced expression of several inflammatory cytokines. Deletion of TRPV4 diminished ROS production and Akt/mTOR phosphorylation. In vitro experiments showed that IMQ caused a concentration-dependent increase in autophagy, characterized by an initial increasing phase followed by a declining phase in primary keratinocytes. IMQ-induced autophagic activity was enhanced via Calmodulin/Akt pathway suppression while weakened by CaMKKβ/AMPK pathway inhibition. Moreover, blockade of the Calmodulin/Akt pathway significantly reduced IMQ-induced ROS production and psoriasis severity, whereas inhibition of the CaMKKβ/AMPK pathway exacerbated IMQ-induced psoriasis progression through ROS accumulation. Conclusions: Both CaMKKβ/AMPK and Calmodulin/Akt signaling pathways, as downstream components of TRPV4, are involved in IMQ-induced psoriasis: lower IMQ dosage activates AMPK, thereby preventing psoriasis by ROS clearance, whereas higher IMQ dosage activates Calmodulin and exacerbates psoriasis. Our findings reveal the potential values of targeting TRP-related channels in IMQ-induced psoriasis.

Lupus mesenteric vasculitis (LMV) is a gastrointestinal lesion primarily caused by vasculitis associated with systemic lupus erythematosus (SLE). In our preliminary experiments, we found that NZBWF1 (BWF1) mice, a spontaneous SLE mouse model, developed bloody stools when treated with imiquimod, a Toll-like receptor (TLR) 7 agonist. Therefore, in this study, we investigated the effects of the continuous application of a TLR7/8 agonist resiquimod (R848) on the gastrointestinal tract in BWF1 mice. To address this, 8-week-old female BWF1 mice were treated with R848 three times weekly for up to 6 weeks. We found that R848-treated mice developed intestinal vasculitis. In addition, these mice exhibited significantly increased serum autoantibody levels and accelerated SLE pathology. Because these symptoms closely resemble human LMV pathology, we established this as a novel inducible LMV mouse model. To elucidate the mechanisms underlying the onset and exacerbation of LMV, we analyzed changes in the intestinal environment. LMV-induced mice showed altered intestinal microbiota and increased fecal levels of propionic acid, an intestinal microbiota metabolite. To investigate the effect of bacteria on LMV pathogenesis, we treated LMV-induced mice with broad-spectrum antibiotics and found that this treatment tended to suppress LMV pathology early in the induction period. Furthermore, propionate administration appeared to attenuate intestinal vasculitis in these mice. Thus, we found that increased intestinal propionate contributes to attenuating LMV pathology. In conclusion, we established an inducible LMV mouse model by R848 treatment of BWF1 mice. Using this induced LMV mouse model, the pathophysiology of LMV can be analyzed in detail. Additionally, our findings suggest that bacteria influence the induction and exacerbation of LMV pathogenesis, and that intestinal propionate may be involved in maintaining homeostasis. In the future, this LMV mouse model may contribute to the development of new diagnostic and therapeutic methods.

Vulvar intraepithelial neoplasia (VIN) is divided into human papillomavirus (HPV)-associated lesions (undifferentiated VIN, high-grade squamous intraepithelial lesion) and HPV-independent VIN (predominantly differentiated VIN). This new WHO classification is essential for the diagnostics, treatment and prognosis. While 90% of cases seen in practice are high-grade intraepithelial lesions (HSIL), dVIN cases are less common (10%), more difficult to diagnose and carry a higher risk of progression to cancer. The lichen sclerosus that most often underlies these lesions is responsible for these characteristics. The distinction between the two lesions is made using p53 and p16 immunohistochemistry on biopsy/excision specimens. Analogous to VIN, invasive carcinomas are also divided into HPV-associated and HPV-independent tumors. Here too, HPV-independent changes are associated with a worse prognosis. The treatment of dVIN is surgical, while treatment of uVIN can be ablative, surgical or medicinal (imiquimod being preferred). The recurrence rate is high regardless of the treatment chosen. Lifelong follow-up is therefore essential. In the case of an invasive carcinoma the majority of patients can be curatively treated with surgery alone. In cases of lymphatic metastasis, adjuvant chemo(radio)therapy is generally administered; in very advanced disease, particularly when continence function is threatened, primary chemoradiotherapy can also be used. Primary prevention of HPV-induced lesions is highly effective through primary HPV vaccination. Secondary prevention of dVIN/HPV-independent invasive carcinoma appears to be achievable through consistent maintenance therapy of the underlying lichen sclerosus with highly potent topical corticosteroids.

Dysbiosis of the gut microbiota has been demonstrated to trigger immune responses that may heighten psoriasis susceptibility. However, conventional therapies for psoriasis are often limited by significant side effects. Ginsenoside Rk3 (Rk3), a bioactive triterpenoid glycoside compound derived from natural ginseng, has shown promise as a potent immunomodulator and gut regulator. Therefore, this study aims to investigate the potential protective effect of Rk3 against psoriasis, with a focus on the gut microbiota modulation and immune response regulation. Network pharmacology was first employed to predict potential targets for the action of Rk3 on psoriasis and an imiquimod (IMQ)-induced psoriasis mice model was used to investigate the palliative effect of Rk3 on psoriasis. Our results reveal that Rk3 restores gut microbiota homeostasis, especially modulating the abundance of Akkermansia muciniphila and Parabacteroides distasonis, and effectively alleviates IMQ-induced psoriasis through gut microbiota-dependent mechanisms. Furthermore, Rk3 exerts a regulatory effect on aberrant amino acid metabolism, suppressing glutamine catabolism while enhancing short-chain fatty acids (SCFAs) biosynthesis. Rk3-mediated regulation of glutamine metabolism exerts an inhibition effect on the conversion of glutamine to glutamate, suppresses Th17 cell differentiation and alleviates psoriasis via the IL-6/JAK1-STAT3 signaling axis. Overall, our research elucidates Rk3's mechanism of action in ameliorating psoriasis and highlights its potential as a gut microbiota modulator for psoriasis treatment.

Toll-like receptor 7 (TLR7) agonists are widely used as immunomodulatory agents, yet their direct effects on T cells remain incompletely understood. Here, we investigated the effects of imiquimod (IMQ) on purified murine CD4[+] T cells using TLR7-deficient mice and pharmacological approaches. IMQ elicited both activating and suppressive responses in CD4[+] T cells. Low concentrations modestly enhanced cell expansion, whereas higher concentrations reduced cell expansion and induced apoptosis in a dose-dependent manner. The suppressive and pro-apoptotic effects were preserved in TLR7-deficient CD4[+] T cells, indicating that these effects are TLR7-independent. In contrast, IMQ-induced upregulation of the early activation marker CD69 was completely abolished in TLR7-deficient CD4[+] T cells, demonstrating strict TLR7 dependence. We further found that thymidine and thymidine-containing oligodeoxynucleotides attenuated IMQ-induced suppression of CD4[+] T cell expansion and apoptosis, while having little effect on CD69 induction. These findings demonstrate that IMQ elicits separable TLR7-dependent and TLR7-independent responses in murine CD4[+] T cells and show that thymidine selectively attenuates the TLR7-independent suppressive and apoptotic effects of IMQ.

The chronic failure of psoriasis treatment strongly recommends a tailored biocompatible therapeutic platform considering the immunological and inflammatory factors of psoriasis pathogenesis. This strategy recommends the utilization of natural phytomolecule of piceatannol due to its healing cutaneous potential, mesenchymal Stem cell-derived exosomes as a regenerative natural nanocarriers and a hydrogel facilitating prolonged release. This work aimed to augment the anti-psoriatic pattern of piceatannol utilizing the mesenchymal stem cells derived exosomes via topical delivery to imiquimod-induced psoriatic mice skin. The formulated exosomal piceatannol platforms were assayed for particle size analysis, entrapment efficiency, flow cytometry analysis, functional size of 137.6 nm, zeta potential of -61.4 ± 6.04 mV, PDI of 0.331, >97% positive expression of all the three tetraspanin markers (CD9, CD63, CD81), entrapment efficiency of 32.8 ± 1.7%, prolonged cumulative release reaching 37.5% after 72 h and satisfactory characterization of 2% w/w carboxymethylcellulose hydrogel. In vivo experimental estimation of the anti-psoriatic activity was conducted and supported by molecular analysis of IL-17, TNF-α, and pSTAT3 levels. mRNA expression of JAK3 was analyzed to explore the targeting of Janus kinase/STAT3. The findings revealed the promising anti-psoriatic activity of the exosomal piceatannol, supported by molecular potential in reducing the mentioned cytokine levels, targeting of JAK/STAT3 pathway and histopathological healing pattern in the psoriasis-induced skin. In conclusion, piceatannol was successfully shown to have a promising regenerative anti-psoriatic profile when loaded as an exosomal hydrogel.

Anal dysplasia and anal cancers are predominantly caused by high-risk types of the human papillomavirus. Lesions are mostly asymptomatic and disproportionately affect high-risk populations such as people living with HIV, women with a history of vulvar (pre)cancer, and long-term immunosuppressed individuals. For these risk groups, the incidence of anal cancer is up to 100 times higher, which is why screening is recommended in the S2k guideline completed in 2024. However, it should be noted that two-thirds of anal cancers occur in older women without HIV, for whom scalable screening strategies do not yet exist due to a lack of feasible triaging methods. The ANCHOR study provided crucial evidence that timely diagnosis and treatment of high-grade anal dysplasia can significantly reduce the risk of anal cancer. To diagnose anal dysplasia, the German-Austrian guidelines recommend a two-stage process: after initial triaging using medical history, cytology, and HPV typing, high-resolution anoscopy (HRA) with biopsy represents the gold standard for diagnosis. Therapeutically, destructive methods (such as electrocautery or trichloroacetic acid) and local immunomodulatory therapies (imiquimod) are used. Cure rates after a single treatment session are relatively low at 10-30%; multiple treatment cycles are often necessary to clear high-grade anal dysplasia. Combining different therapeutic modalities is frequently a feasible strategy. For advanced anal cancer, recent studies such as POD1UM-303/InterAACT‑2 (immunotherapy with retifanlimab), as well as procedures like plasma HPV-ctDNA measurement (liquid biopsy) and dose-escalated/sparing radiation therapy, show promising results and give a perspective for the ongoing revision of the S3 guideline on anal cancer.

Psoriasis is a chronic inflammatory skin disease with clear spatial stratification, featuring epidermal keratinocyte hyperproliferation and inflammatory infiltration across epidermal and dermal compartments. High oxygen consumption by keratinocytes and inflammatory cells, together with restricted oxygen diffusion caused by epidermal thickening, renders psoriatic lesions hypoxic. Hypoxia further couples with excessive reactive oxygen species (ROS), forming a vicious cycle that drives disease progression. In this study, we found that the hypoxic microenvironment was closely associated with reduced responsiveness of keratinocytes to methotrexate (MTX), a classical anti-psoriasis drug in clinic. Then, a "spatiotemporal-release" bilayer microneedle (MN) patch was developed. The patch consisted of dissolvable poly(vinylpyrrolidone) (PVP) needle tails loaded with MTX, together with phenylboronic acid-crosslinked hydrogel needle tips encapsulating MnO2 nanozymes (MnO2 NMs). After insertion into the skin of imiquimod (IMQ)-induced psoriasis-like mice, the needle tails rapidly released MTX for early epidermal intervention, whereas the hydrogel tips released MnO2 NMs in response to the high-ROS dermal microenvironment. By scavenging ROS and generating oxygen, MnO2 NMs could break the hypoxia-ROS vicious cycle, thereby improving the response of keratinocytes to MTX. In vivo experiments showed that this MN patch improved the therapeutic effect of MTX, and providing a new perspective for psoriasis treatment.