Radiotherapy (RT) resistance remains a significant challenge in esophageal squamous cell carcinoma (ESCC). While Nrf2 is known to mediate antioxidant defense, its role in modulating the immunogenicity of radiotherapy-induced cell death is poorly understood.
We established a spontaneous esophageal cancer model using genetically engineered mice with conditional knockout of Nrf2, and analyzed the tumor immune microenvironment by single-cell RNA sequencing. In vitro, we performed co-culture experiments using CRISPR/Cas9-mediated Nrf2-knockout esophageal cancer cell lines with dendritic cells and T cells to validate immune activation. In addition, in vivo validation was conducted using a mouse subcutaneous tumor model.
ScRNA-seq revealed that Nrf2 deficiency significantly remodeled the myeloid compartment, characterized by a population shift from Folr2 + to Mrc1 + macrophages and an expansion of effector T cells. Mechanistically, Nrf2 deletion downregulated the expression of Gpx2, impairing antioxidant defenses. This sensitized ESCC cells to RT, triggering the release of immunogenic cell death (ICD) markers, including ATP, HMGB1, and surface calreticulin (CRT). In tumor-DC-T cell co-culture systems, Nrf2-deficient cells stimulated dendritic cells (DCs) to secrete IP-10 (CXCL10), which was indispensable for the recruitment and activation of CD8 + T cells. Finally, in vivo experiments confirmed that Nrf2 deficiency enhanced radiosensitivity and promoted CD8 + T cell infiltration.
Our findings identify the Nrf2-Gpx2 axis as a master regulator of immunogenicity in ESCC. Targeting this axis represents a promising strategy to convert "cold" tumors into "hot" environments, thereby improving the efficacy of radiotherapy and immunotherapy.
© 2026. The Author(s).

Extracellular vesicles (EVs) are nano-sized, membrane-delimited, particles released by cells that carry signaling macromolecules. A major pathway of EV production is potentiated by neutral sphingomyelinase 2 (SMPD3/nSMAse2), an enzyme that generates ceramide from sphingomyelin. In our attempt to study this pathway in adipocytes of male mice, we discover that the elimination of SMPD3 from adipocytes in vivo triggers a signal to surrounding immune cell-like preadipocytes to release EVs that carry SMPD3 mRNA. This results in a widespread increase in SMPD3 mRNA in purified null adipocytes without a change in the transcripts of other enzymes involved in ceramide metabolism. These results point to a selective mechanism by which specific mRNA molecules are acquired from the microenvironment to a level that can restore expression of mRNA and protein in a cell that is depleted of the corresponding genetic information.
© 2026. The Author(s).

Cell polarity is essential for maintaining intestinal epithelial organization and function. Here we show that combined loss of polarity by epithelial loss of Cdc42 with oncogenic Kras expression in mice causes small intestine failure leading to weight loss, inflammation, epithelial necroptosis, and lethality. These phenotypic defects are characterized by a loss of intestinal stem cells, disrupted epithelial architecture, altered hippo signaling, elevated inflammatory cytokines, and activation of necroptotic cell death, that closely resemble necrotizing enterocolitis (NEC). Single-cell transcriptomic analysis reveals a coordinated dysregulation of polarity machinery, inflammatory pathways, and necroptosis program. Suppression of YAP, IL-1, TNFα signaling or necroptosis rescues the intestinal pathology. Similar NEC-like phenotypes arise when Cdc42 loss and oncogenic Kras activation are initiated from intestinal stem cells. These findings provide mechanism insights involving polarity-YAP-IL1/TNFα signaling induced necroptosis for the synergistic effect of hyperactivation of Kras signaling and loss of polarity in disrupting intestinal epithelia.
© 2026. The Author(s).

Non-small cell lung cancer (NSCLC) is the most frequent type of lung cancer, and its main treatments include chemotherapy with genotoxic drugs and immunotherapy. Central to the cellular response to genotoxic stress is the DNA damage response (DDR) network, regulated by key kinases such as ataxia-telangiectasia mutated and Rad3-related (ATR). Herein, we tested the hypothesis that inhibition of ATR enhances the cytotoxicity of genotoxic agents and the antitumor immune response.
DDR-related parameters and redox status, expressed as GSH/GSSG ratio, and apurinic/apyrimidinic lesions, were evaluated in human (A549, H1299) and murine (LLC) NSCLC cell lines after co-exposure to ATR inhibitor (AZD6738) and ultraviolet C (UVC) irradiation or cisplatin. Using a syngeneic LLC model, treatments of AZD6738 alone or in combination with cisplatin and/or anti-programmed cell death 1 antibody (anti-PD1) were examined.
In all cell lines, combined treatment with AZD6738 and cisplatin or UVC irradiation markedly decreased cell viability, DNA repair efficiency, and GSH/GSSG ratios; increased drug-induced DNA damage; and augmented apurinic/apyrimidinic lesions. In vivo, following treatment with AZD6738 and cisplatin, flow cytometry analysis performed in tumor cells revealed an increased infiltration of CD3+ and CD8+ T cells, with the triple combination of AZD6738, cisplatin, and anti-PD1 achieving the strongest antitumor effect. The CD3+CD4-CD8- double-negative (DN) T cell population in tumor samples also emerged as a contributing factor in this context.
These results demonstrate that ATR blockade concurrently enhances the efficacy of genotoxic agents and immune checkpoint inhibitors, thus paving the way for combination therapies in NSCLC.

Vaso-occlusive crises, thrombosis, inflammation, and immune dysregulation contribute to organ damage and poor outcomes in sickle cell disease (SCD). Because neutrophils and dysregulated extracellular trap formation (NETosis) contribute to sickle pathophysiology, and the spleen tyrosine kinase (Syk) signaling pathway is a key driver of NETosis, we investigated the effect of targeting Syk with fostamatinib (R788). Specifically, we studied the effect of a selective Syk inhibitor, R788, on hematologic and biochemical parameters, NETosis, platelet P-selectin expression, and platelet-neutrophil aggregate formation in Townes sickle mice at baseline and after exposure to pathophysiological stressors (tumor necrosis factor α [TNF-α] and hypoxia-reoxygenation). Our results showed that at baseline R788 impaired hematopoiesis, and worsened anemia and neutropenia in sickle mice. Additionally, R788 at nontoxic doses had little, if any, effect on NETosis and platelet activation induced by TNF-α or hypoxia-reoxygenation. Severe anemia and neutropenia induced by R788 in the sickle mouse model suggests that concomitant use of Syk inhibitors with hydroxyurea in patients with SCD should be approached cautiously. Further research is required to clarify the benefits and risks of selective Syk inhibition in SCD and other hemolytic conditions exhibiting stress hematopoiesis.