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Alzheimer¡¯s disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer¡¯s disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01859-8.

Tumor patients often exhibit limited responses to immunotherapy owing to the low immunogenicity and immunosuppressive environment of tumors. Our previous studies revealed that cryo-thermal therapy caused tumor cell rupture due to mechanical compression, notably causing the release of a substantial amount of DAMPs (danger-associated molecular patterns), such as heat shock protein 70, calreticulin and high-mobility group box protein 1; the release of these DAMPs increased myeloid cell maturation, thereby reshaping the systemic immune environment and ultimately inducing durable CD4+ T helper type 1 (Th1) cell-dominated antitumor immunity. In fact, under conditions of mechanical stress and rapid temperature changes, the disruption of tumor cells caused by cryo-thermal therapy results in extensive deoxyribonucleic acid (DNA) damage and the rapid release of substantial amounts of DNA. Consequently, tumor-derived DNA, which potently activates innate immunity by engaging multiple DNA sensors, plays a pivotal role in orchestrating antitumor immunity. We hypothesized that cryo-thermal therapy induces the transient release of high levels of DNA, which modulates CD11b+ myeloid cell function, subsequently influencing CD4+ Th1-cell dominated antitumor immune responses. In this study, a B16F10 melanoma model was established, and DNA concentrations were measured at different time points after cryo-thermal therapy. Deoxyribonuclease I (DNase I) was subsequently administered immediately following cryo-thermal therapy to deplete extracellular DNA, allowing an investigation of the role of DNA in regulating CD11b+ myeloid cell function and CD4+ T cell differentiation. The phenotype and function of CD11b+ myeloid cells and CD4+ T cells were assessed by flow cytometry, RNA sequencing, and cell culture in vitro. Our studies confirmed that cryo-thermal therapy triggered a transient release of high levels of DNA, which was internalized by CD11b+ myeloid cells via C-type lectin receptors and subsequently sensed by inflammasomes. Then, the intracellular sensing of DNA induced the production of the mature form of interleukin (IL)-18, ultimately promoting the Th1 differentiation of CD4+ T cells. This study highlights the pivotal role of DNA release after cryo-thermal therapy in driving CD4+ Th1 cell-dominant antitumor immunity.

Liver metastasis (LM) poses a significant challenge in cancer treatment, with limited available therapeutic options and poor prognosis. Understanding the dynamics of tumor microenvironment (TME) and immune interactions is crucial for developing effective treatments. We find that WNT11 promoted CD8+ T-cell exclusion and suppression, which was correlated with poor prognosis in LM. Mechanistically, WNT11-overexpressing tumor cells directly reduce CD8+ T-cell recruitment and activity by decreasing CXCL10 and CCL4 expression through CAMKII-mediated ¦Â-catenin/AFF3 downregulation. WNT11-overexpressing tumor cells promote immunosuppressive macrophage polarization by inducing IL17D expression via the CAMKII/NF-¦ÊB pathway, which result in CD8+ T-cell suppression. Moreover, CAMKII inhibition increases the efficacy of anti-PD-1 therapy in mouse model of LM. Serum expression of WNT11 is identified as a potential minimally invasive biomarker in the management of colorectal cancer-LM with immunotherapy. Our findings highlight WNT11/CAMKII axis as a critical regulator of the TME and a promising target for immunotherapy in patients with LM. Activation of the WNT/¦Â-catenin signaling pathway has been associated with immune evasion in several cancer types. Here the authors show that expression of WNT11, a member of the non-canonical WNT signaling pathway, is associated with CD8?+?T cell exclusion and resistance to immune checkpoint inhibitors in liver metastasis.