AtaGenix September 2026 Publication Roundup: Ten Studies Across Oncology, Immunology and Pathogen Research

Triple-negative breast cancer (TNBC) lacks well-defined molecular targets, and taxane-based chemotherapy remains the mainstay of treatment, limited by dose-dependent toxicity and acquired resistance. γδ-T cells kill tumor cells directly without MHC restriction, and their infiltration in TNBC is associated with better prognosis, but whether they act synergistically with taxanes has been unclear. Using TNBC cell lines and their paclitaxel-resistant sublines, patient-derived organoids and mouse xenograft models, together with transcriptomic and proteomic profiling, gene knockdown and in vivo treatment experiments, the authors found that low-dose paclitaxel and docetaxel suppressed tumor cell proliferation without harming γδ-T cells; instead, the drugs promoted their expansion and enhanced their effector function, and the combination showed synergistic antitumor activity both in vitro and in vivo. Mechanistically, taxane treatment induced γδ-T cells to secrete ANXA6 and PPP2R1A. Both proteins are highly expressed in breast cancer, correlate with better survival and are enriched in cell death-related pathways; knocking down either gene reduced the killing capacity of the conditioned medium, adding recombinant protein restored it, and both proteins induced apoptosis in TNBC cells directly. The synergy held in resistant cell lines, in organoids from chemotherapy-refractory patients and in resistant xenografts, and it eliminated cancer stem cell-like populations. The authors conclude that low-dose taxanes reprogram γδ-T cells to couple chemotherapy with immune killing, offering a route to overcoming resistance in TNBC while reducing chemotherapy toxicity.

Glioblastoma (GBM) is the most common malignant brain tumor in adults, and excessive mTORC1 activation is one of its hallmarks, yet how mTORC1 relays nutrient signals to the DNA repair machinery in the nucleus has remained unclear. DDA1, a regulatory subunit of the CRL4^CSA ubiquitin ligase complex, participates in transcription-coupled nucleotide excision repair and is upregulated in several cancers, but its mechanism is undefined. Working with glioma cell lines and orthotopic xenograft models and combining affinity purification–mass spectrometry, phosphoproteomics, transcriptomics and gene editing, the authors found that DDA1 binds the mTORC1 core component Raptor directly at the lysosomal surface, although it does not act upstream of mTORC1. Amino acid stimulation induced mTORC1-dependent phosphorylation of DDA1 at serine 33, a modification controlled by both RagA and Rheb and highly conserved across vertebrates. Once phosphorylated, DDA1 moved from the cytoplasm into the nucleus, bound the CRL4^CSA complex more strongly and promoted nucleotide excision repair after UV damage, while a phospho-deficient mutant failed to restore clonogenic survival; transcriptomic analysis also suggested the pathway regulates a set of metabolic genes. In vivo, DDA1 knockout suppressed tumor growth, increased DNA damage and blunted the tumor response to nutrient supplementation, and clinical database analysis linked high DDA1 expression to poor prognosis. The authors propose that the mTORC1–DDA1^S33–DNA repair axis connects nutrient sensing to genome maintenance and may be a therapeutic target in glioma.

Coordination between the light and dark reactions of photosynthesis underpins both efficiency and photoprotection, but how plants control it is not well understood. Calcium-dependent protein kinases (CPKs) are broadly involved in stress signaling, and the authors had previously observed that the rice mutant oscpk12 is sensitive to high light, suggesting a role in light acclimation. Using wild-type japonica rice, the oscpk12 mutant and OsAtpD1 transgenic lines, together with protein interaction assays, in vitro kinase reactions, mass spectrometry, chloroplast isolation and chlorophyll fluorescence measurements, the study found that mutant plants senesced early under high light, with reduced chlorophyll content, net photosynthetic rate and maximum photochemical efficiency of photosystem II, and with elevated reactive oxygen species and malondialdehyde. Mechanistically, OsCPK12 interacts with OsAtpD1, the δ subunit of chloroplast ATP synthase, and phosphorylates a serine residue in its transit peptide; when this site was mutated to a non-phosphorylatable form, OsAtpD1 was retained in the cytoplasm, whereas a phosphomimetic form entered the chloroplast normally. Accordingly, ATP synthase activity, electron transport rate and the transmembrane proton gradient were all reduced in the mutant, in lines overexpressing the non-phosphorylatable form and in OsAtpD1 knockdown lines, while OsCPK12 overexpression lines exceeded wild type, and overexpression of the phosphomimetic form rescued the early senescence phenotype. The authors conclude that light-induced OsCPK12 phosphorylates OsAtpD1 to promote its import into the chloroplast, sustaining ATP synthase activity and proton gradient homeostasis and thereby enabling photosynthetic acclimation and photoprotection under light stress.

Pollen allergy affects roughly a third of the world's population. Existing allergen immunotherapy gives inconsistent results, can trigger IgE-mediated reactions and rarely establishes lasting tolerance. mRNA vaccines offer programmable antigens and a lower risk of IgE cross-linking, but the lipid nanoparticles used to deliver them are themselves adjuvant-active and cause non-specific inflammation that works against tolerance. This study modified both the antigen sequence and the delivery system: a non-secreted mRNA encoding the major mugwort allergen, with the signal peptide removed and the invariant chain fused, was designed so that the antigen is presented intracellularly through the MHC II pathway, while screening of PEG lipid chain length and the addition of mannose modification produced a low-inflammation formulation targeted to antigen-presenting cells. After subcutaneous administration the formulation was expressed mainly in the liver, where it created a local tolerogenic environment marked by elevated regulatory cytokines; dendritic cells adopted an MHC II-high, costimulatory molecule-low tolerogenic phenotype, and allergen-specific regulatory T cells expanded in the spleen. In both therapeutic and prophylactic mouse models of mugwort pollen allergy, the vaccine reduced allergic symptoms and lung inflammation, lowered specific IgE and corrected IgG subclass ratios. The authors present the platform as a modular strategy for inducing allergen-specific tolerance, while noting that the durability of that tolerance and the underlying causal mechanism still require further work.

Systemic lupus erythematosus (SLE) affects multiple organs. Adaptive immune abnormalities have been studied extensively, but the contribution of innate subsets such as macrophages to tissue damage remains unclear. Folate receptor 2 (FOLR2) marks proinflammatory macrophages in other inflammatory diseases, and urinary FOLR2 correlates with lupus nephritis and disease activity, yet its function has not been defined. Integrating public single-cell and transcriptomic datasets, clinical skin lesion and kidney biopsy specimens, lupus mouse models and in vitro macrophage experiments, the study found that total dermal macrophage numbers in SLE lesions were comparable to controls, but the FOLR2-positive subset was markedly expanded and became dominant — a pattern absent in discoid lupus erythematosus. Expression was similarly elevated in lupus nephritis kidney tissue, and the density of these cells in skin lesions correlated with disease activity scores. Compared with cells from healthy donors, SLE-derived FOLR2-positive macrophages showed a proinflammatory phenotype with multiple inflammatory pathways activated; after immune complex stimulation they secreted more proinflammatory cytokines, showed reduced phagocytic capacity and upregulated antigen presentation and costimulatory molecules. The authors then built a folate-targeted nanocarrier that selectively depleted and inactivated this subset, lowering autoantibody levels in mice, reducing skin and kidney pathology, improving the urinary albumin-to-creatinine ratio, shifting the Th1/Th17 ratio downward and increasing regulatory T cells, with an acceptable preliminary safety profile. The authors conclude that FOLR2-positive macrophages are a key pathogenic subset driving skin and kidney damage in SLE and that targeted depletion offers a precise alternative to broad immunosuppression.

Several sarbecoviruses closely related to SARS-CoV-2 have been detected in Malayan pangolins, but their pathogenicity and cross-species transmission risk had not been systematically assessed. This study compared two pangolin-derived coronaviruses, MpCoV-GD and MpCoV-GX, side by side with SARS-CoV-2 in human cell lines, organoids and hACE2 transgenic hamsters. Both viruses replicated efficiently in human cells and organoids, though less so than SARS-CoV-2, and their spike proteins mediated weaker membrane fusion. In hamsters, MpCoV-GD produced lung pathology similar to SARS-CoV-2, with extensive alveolar parenchymal damage, whereas MpCoV-GX caused mainly mild inflammatory infiltration and alveolar wall thickening; both viruses transmitted by direct contact and by aerosol, although infectivity was clearly reduced by the aerosol route. In the treatment and prevention assessment, remdesivir and molnupiravir inhibited both viruses, and sera from COVID-19 convalescents and from mice immunized with inactivated vaccine cross-neutralized both. The monoclonal antibody S309 showed broad neutralizing activity, while REGN10933 and REGN10987 were effective only against MpCoV-GD, owing to extensive amino acid substitutions in the receptor-binding domain epitopes of MpCoV-GX. The authors conclude that pangolin-derived sarbecoviruses are generally less pathogenic and less transmissible than SARS-CoV-2, and that existing drugs and immunity offer some cross-protection, while continued surveillance of wildlife viruses remains necessary.

Hemorrhagic disease caused by grass carp reovirus (GCRV) is highly lethal in grass carp and rare minnow, with extensive bleeding across multiple tissues, and reducing hemorrhage is central to improving survival. The protein phosphatase 1 regulatory subunit PPP1R3G has been studied mainly in glycogen synthesis and lipid metabolism, and its role in fish innate immunity was unknown. Using grass carp kidney CIK cells, stable K562 lines, HEK293T cells, ppp1r3g-knockout rare minnow and ppp1r3g chimeric grass carp, together with co-immunoprecipitation–mass spectrometry, truncation and site-directed mutagenesis, immunohistochemistry and immunofluorescence, the authors showed that poly(I:C) and GCRV stimulation upregulate ppp1r3g, while knockdown suppresses viral replication and raises type I interferon levels, indicating that Ppp1r3g negatively regulates the RLR pathway through interactions with Rig-I, Mda5 and Traf6. In vivo, fish lacking the gene were markedly more resistant to GCRV, showed reduced hemorrhage and upregulated immune-related genes. Mechanistically, Ppp1r3g binds the EL17 fragment of 14-3-3ζ via Ser36/Ser37 in its PP1c domain, and integrin β3 (Itgb3) binds the same fragment, so the two compete; Ppp1r3g also promotes proteasomal degradation of Itgb3 in a dose-dependent manner, preventing formation of the 14-3-3ζ–Itgb3 complex and suppressing platelet activation and the downstream coagulation cascade. The authors conclude that GCRV induces Ppp1r3g to suppress antiviral immunity and coagulation at the same time, worsening hemorrhage, and that this axis is a potential target for controlling the disease.

Edwardsiella piscicida is a Gram-negative pathogen that infects many commercially farmed fish and can also infect humans. Its type III secretion system (T3SS) injects effector proteins into host cells to interfere with immune signaling and is central to virulence, but which effectors drive the strong inflammatory response, and how, had not been established. Using the mouse macrophage line J774A.1, HEK293T cells, primary head kidney leukocytes from yellow catfish and zebrafish larvae, together with deletion strains, co-immunoprecipitation, ubiquitination analysis and domain truncation, the study showed that the T3SS effector EseJ activates the NF-κB pathway and promotes the transcription and secretion of IL-1β, IL-6 and other proinflammatory cytokines, with an eseJ deletion strain inducing markedly less. Mechanistically, EseJ acts on two ubiquitin-dependent steps through two independent domains: its N-terminal region (residues 1–242) binds the NF-κB subunit p65 and prevents K48-linked polyubiquitination and proteasomal degradation, maintaining higher levels of total and phosphorylated p65 and promoting nuclear translocation and transcriptional activity; its middle region (residues 243–532) binds both TAK1 and TRAF6, acting as a molecular scaffold that stabilizes the TRAF6–TAK1 complex, enhances TRAF6-mediated K27-linked ubiquitination of TAK1 and drives TAK1 phosphorylation and activation of the downstream IKK–IκB–NF-κB cascade, an effect lost when TAK1 is inhibited. Zebrafish infection experiments confirmed that EseJ is required for cytokine production in vivo. The authors conclude that EseJ amplifies NF-κB-dependent inflammation by targeting p65 and TAK1 simultaneously, and that because its homologs are conserved in other Gram-negative bacteria, the mechanism may be a general one.

Tick-borne encephalitis virus (TBEV) causes an estimated 10,000 to 15,000 reported cases each year. Existing inactivated vaccines mainly induce humoral immunity, require multiple doses and offer limited duration of protection, which is generally attributed to the weak T cell response they elicit. Artificial multi-epitope immunogens are a plausible route to a T cell vaccine, but how the spacer sequences linking epitopes affect immunogenicity has largely been addressed by theoretical prediction, without systematic comparison within a single epitope set. The authors screened flavivirus T cell epitopes from the Immune Epitope Database, aligned them against the TBEV proteome and used epitope prediction tools to select 13 oligopeptides from the E, NS1, NS3 and NS5 proteins, assembling them into multi-epitope immunogens in three ways: with an algorithm-optimized alanine-containing spacer, with a flexible GPGPG spacer and with no spacer at all, each fused to ubiquitin at the N terminus and built into a corresponding DNA vaccine. Structural prediction showed little difference between the three designs, but protein expression analysis indicated that the GPGPG construct is processed quite differently and exists only as degradation products. After electroporation-based immunization of mice, the alanine-spacer and no-spacer groups both induced significant IFN-γ-secreting cell responses, while the GPGPG group responded weakly; none produced antibodies against the E protein, consistent with a design containing only T cell epitopes. The authors conclude that spacer choice substantially affects the immunogenicity of multi-epitope vaccines and that GPGPG is unsuitable in this system, while noting that the findings so far come from a single mouse strain.

Age-related macular degeneration (AMD) is the leading cause of vision loss in older adults, oxidative stress is considered its core pathogenic mechanism, and effective prevention or treatment is still lacking. VEGFB is the member of the VEGF family with both antioxidant and neuroprotective activity, and its main functional isoform VEGFB167 accounts for more than 80% of transcripts, but low yields in prokaryotic expression have made large-scale preparation difficult. This study established a temperature-induced, IPTG-free expression system in E. coli BL21 using the pBV220 vector; the target protein accumulated efficiently as inclusion bodies and, after nickel affinity chromatography, refolding and gel filtration, yielded active protein of approximately 97% purity. In a hydrogen peroxide-induced oxidative injury model in retinal pigment epithelial cells, VEGFB167 reduced membrane damage and lipid peroxidation in a concentration-dependent manner, lowered reactive oxygen species, raised antioxidant enzyme activity and the expression of related genes, suppressed apoptosis and restored DNA replication and proliferation. The authors conclude that the workflow reliably produces biologically active VEGFB167 and supports its development as a candidate therapeutic for oxidative damage-related disease, while noting that the evidence comes only from in vitro cell experiments, that the upstream receptor and downstream signaling remain undefined and that in vivo efficacy has yet to be demonstrated.