Search Results (318)

Influenza B viruses, divided into B/Victoria and B/Yamagata lineages, have not had B/Yamagata isolates after 2020. A study evaluated immunity to influenza B surface antigens hemagglutinin (HA) and neuraminidase (NA) in 138 patient sera from 2023 and 23 pairs of sera from 2018 to 2019 vaccine recipients. The phylogenetic tree of the influenza B virus, based on HA and NA genes, shows that the Yamagata lineage evolves gradually, while the Victoria lineage exhibits rapid mutations with short branches. In 2023, mean levels of antibodies to HA and NA of B/Yamagata virus were higher than to B/Victoria, despite no cases of B/Yamagata lineage isolation after 2020. The titers of antibodies to NA of B/Yamagata statistically significantly differed among individuals born before and after 1988. Among patients examined in 2018–2019, neuraminidase-inhibiting (NI) antibody titers before vaccination were higher to B/Yamagata than to B/Victoria, and NI antibodies to B/Victoria and B/Yamagata positively correlated with neutralizing antibodies to B/Victoria virus before and after vaccination. Immunity to B/Yamagata virus was stronger in 2023, despite no isolation since 2020, probably due to the presence of cross-reactive antibodies from B/Victoria infections or vaccinations. Antibodies to NA of B/Victoria and B/Yamagata in 2023 correlated significantly in patients born before 1988, potentially supporting the concept of ‘antigenic sin’ phenomenon for influenza B viruses. The fact that NI antibody titers to B/Victoria and B/Yamagata correlated with neutralizing antibody titers to B/Victoria may suggest broad cross-protection. Studying influenza B virus NA antigenic properties helps understand the evolution and antigenic competition of HA and NA. Full article

Mineral imbalances in livestock can critically impair growth, immunity, and productivity. Yaks inhabiting the Qinghai–Tibetan Plateau face unique environmental challenges, including high-altitude-induced nutrient variability. This study investigated the status of mineral elements and their correlations with altitude in healthy yak calves across five regions in Ganzi Prefecture, located at elevations ranging from 3100 to 4100 m. Hair and serum samples from 35 calves were analyzed for 11 essential elements (Na, K, Ca, Mg, S, Cu, Fe, Mn, Zn, Co, and Se). The results revealed widespread deficiencies. Key deficiencies were identified: hair Na and Co were significantly below references value (p < 0.05), and Se was consistently deficient across all regions, with deficiency rates ranging from 35.73% to 56.57%. Serum Mg and Cu were generally deficient (Mg deficiency > 26% above 3800 m). S, Mn (low detection), and Co were also suboptimal. Serum selenium deficiency was notably severe in lower-altitude areas (≤59.07%). Significant correlations with altitude were observed: hair sodium levels decreased with increasing altitude (r = −0.72), while hair manganese (r = 0.88) and cobalt (r = 0.65) levels increased. Serum magnesium deficiency became more pronounced at higher elevations (r = 0.58), whereas selenium deficiency in serum was more severe at lower altitudes (r = −0.61). These findings indicate prevalent multi-element deficiencies in yak calves that are closely linked to altitude and are potentially influenced by soil mineral composition and feeding practices, as suggested by previous studies. The study underscores the urgent need for region-specific nutritional standards and altitude-adapted mineral supplementation strategies to support optimal yak health and development. Full article

Suckling is crucial for piglet intestinal development and gut health, as it improves resilience during the challenging weaning phase and promotes subsequent growth. IPS, comprising Na⁺/K⁺ ions, whey protein, and glucose, has been shown to have positive effects on animal growth and intestinal health. The objectives of this study were to assess the impact of IPS consumption on the growth performance, immunity, intestinal growth and development, and microbiota structure of suckling piglets. A total of 160 newborn piglets were randomly divided into control and IPS groups, with IPS supplementation starting from 2 to 8 days after birth and continuing until 3 days before weaning. The findings revealed that IPS boosted the body weight at 24 days by 3.6% (p < 0.05) and improved the body weight gain from 16 to 24 days by 15.7% (p < 0.05). Additionally, the jejunal villus height and villus height to crypt depth ratio in the IPS group were notably increased to 1.08 and 1.31 times (p < 0.05), respectively, compared to the control group. Furthermore, IPS elevated the plasma levels of IgA and IgM, reduced the plasma levels of blood urea nitrogen (BUN), and enhanced the content of secretory immunoglobulin A (SIgA) in the jejunal mucosa of suckling piglets. Furthermore, IPS upregulated the mRNA expression of tight junction proteins GLP-2, ZO-1, and Claudin-1 in jejunal tissue, while downregulating the regulatory genes in the Toll-like pathway, including MyD88 and TLR-4 (p < 0.05). The analysis of gut microbiota indicated that IPS altered the relative abundance of gut microbes, with an increase in beneficial bacteria like Alloprevotella and Bacteroides. In conclusion, this study demonstrates that IPS supplementation enhances weaning weight, growth performance, immune function, and intestinal development in piglets, supporting the integration of IPS supplementation in the management of pre-weaning piglets. Full article

Background: Fowl typhoid (FT), a septicemic infection caused by Salmonella Gallinarum (SG), and H9N2 avian influenza are two economically important diseases that significantly affect the global poultry industry. Methods: We exploited the live attenuated Salmonella Gallinarum (SG) mutant JOL3062 (SG: ∆lon ∆pagL ∆asd) as a delivery system for H9N2 antigens to induce an immunoprotective response against both H9N2 and FT. To enhance immune protection against H9N2, a prokaryotic and eukaryotic dual expression plasmid, pJHL270, was employed. The hemagglutinin (HA) consensus sequence from South Korean avian influenza A virus (AIV) was cloned under the Ptrc promoter for prokaryotic expression, and the B cell epitope of neuraminidase (NA) linked with matrix protein 2 (M2e) was placed for eukaryotic expression. In vitro and in vivo expressions of the H9N2 antigens were validated by qRT-PCR and Western blot, respectively. Results: Oral immunization with JOL3121 induced a significant increase in SG and H9N2-specific serum IgY and cloacal swab IgA antibodies, confirming humoral and mucosal immune responses. Furthermore, FACS analysis showed increased CD4+ and CD8+ T cell populations. On day 28 post-immunization, there was a substantial rise in the hemagglutination inhibition titer in the immunized birds, demonstrating neutralization capabilities of immunization. Both IFN-γ and IL-4 demonstrated a significant increase, indicating a balance of Th1 and Th2 responses. Intranasal challenge with the H9N2 Y280 strain resulted in minimal to no clinical signs with significantly lower lung viral titer in the JOL3121 group. Upon SG wildtype challenge, the immunized birds in the JOL3121 group yielded 20% mortality, while 80% mortality was recorded in the PBS control group. Additionally, bacterial load in the spleen and liver was significantly lower in the immunized birds. Conclusions: The current vaccine model, designed with a host-specific pathogen, SG, delivers a robust immune boost that could enhance dual protection against FT and H9N2 infection, both being significant diseases in poultry, as well as ensure public health. Full article

Background/Objectives: Swine influenza A virus (swIAV), a prevalent respiratory pathogen in porcine populations, poses substantial economic losses to global livestock industries and represents a potential threat to public health security. Neuraminidase (NA) has been proposed as an important component for universal influenza vaccine development. NA has potential advantages as a vaccine antigen in providing cross-protection, with specific antibodies that have a broad binding capacity for heterologous viruses. In this study, we evaluated the immunogenicity and protective efficacy of a tetrameric recombinant NA subunit vaccine in a swine model. Methods: We constructed and expressed structurally stable soluble tetrameric recombinant NA (rNA) and prepared subunit vaccines by mixing with ISA 201 VG adjuvant. The protective efficacy of rNA-ISA 201 VG was compared to that of a commercial whole inactivated virus vaccine. Pigs received a prime-boost immunization (14-day interval) followed by homologous viral challenge 14 days post-boost. Results: Both rNA-ISA 201 VG and commercial vaccine stimulated robust humoral responses. Notably, the commercial vaccine group exhibited high viral-binding antibody titers but very weak NA-specific antibodies, whereas rNA-ISA 201 VG immunization elicited high NA-specific antibody titers alongside substantial viral-binding antibodies. Post-challenge, both immunization with rNA-ISA 201 VG and the commercial vaccine were effective in inhibiting viral replication, reducing viral load in porcine respiratory tissues, and effectively mitigating virus-induced histopathological damage, as compared to the PBS negative control. Conclusions: These findings found that the anti-NA immune response generated by rNA-ISA 201 VG vaccination provided protection comparable to that of a commercial inactivated vaccine that primarily induces an anti-HA response. Given that the data are derived from one pig per group, there is a requisite to increase the sample size for more in-depth validation. This work establishes a novel strategy for developing next-generation SIV subunit vaccines leveraging NA as a key immunogen. Full article

Introduction: Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. Even though surgery and chemotherapy are the mainstay of treatment, immunotherapy, and more specifically anti-tumor vaccination, has gained popularity over the past years due to the lower related toxicity and fewer long-term side effects. Dendritic cell (DC) vaccines have been shown to induce tumor specific cytotoxic T-cell (CTL) responses both in vitro and in vivo; however, due to the nature of the disease, resistance to immunotherapy is often developed. Various modifications, such as the implementation of viral vectors, tumor RNA, or even tumor-specific peptides (neoantigens), have been studied as a means to avoid resistance and enhance the effectiveness of the vaccines. In this review, we aim to assess the effects of neoantigen-loaded DC vaccines (naDCVs) on the immune response against gastric cancer cells. Materials and methods: A thorough literature search was conducted on PubMed and clinicaltrials.gov for studies assessing the efficacy of naDCVs against gastric cancer both in vivo and in vitro. The studies were assessed for eligibility by two independent reviewers based on predetermined inclusion and exclusion criteria. The search was completed following the PRISMA guidelines. Results: Eleven studies were included in our systematic review. In five of the studies, the effects of the naDCVs were tested in vitro; in two and in four they were examined both in vitro and in vivo. The in vitro studies showed that the naDCVs resulted in a more robust immune response against the cancer cells in the study groups compared to the control groups. The in vivo studies conducted on mice showed that tumor volume was reduced in the groups treated with the naDCV compared to the untreated groups. What is more, the cytotoxic effect of CTLs against tumor cells was also increased in the vaccine groups. One of the studies was conducted on humans as a phase I study. The results show increased CTL proliferation and cytokine production in the vaccinated group compared to the control, but no difference regarding the tumor size was observed. Conclusions: Neoantigen-loaded DC vaccines can stimulate a strong immune response against specific gastric cancer cell peptides and enhance tumor cell lysis, therefore hindering or even reversing disease progression, offering great potential for the treatment of patients with gastric cancer. Full article

Fc gamma receptors (FcγRs) control humoral and cellular immune responses and maintain the immune system balance. Functional polymorphisms of FcγRs, whose prevalence was dependent on ethnic origin, were found to be associated with systemic lupus erythematosus (SLE) or kidney injuries in several ethnic groups. We aimed at investigating the association between the functional single-nucleotide polymorphisms (SNPs) of FcγRIIa-H131R (rs1801274), FcγRIIb-I232T (rs1050501), FcγRIIIa-V158F (rs396991) and FcγRIIIb variants (NA1 and NA2) and lupus erythematosus systemic in an indigenous African Caribbean population. We compared the frequencies of the functional SNPs of FCGR2A (FcγRIIa-H131R, rs1801274), FCGR2B (FcγRIIb-I232T, rs1050501), FCGR3A (FcγRIIIa-V158F, rs396991) and FCGR3B variants (FcγRIIIb NA1 and NA2) between lupus and healthy controls in an indigenous African Caribbean population. We highlighted an association between the FCGR3B-NA1/NA1 and FCGR3A-158F alleles and systemic lupus erythematosus, in addition to an association between FCGR2A-131R and lupus nephritis. Furthermore, an increase in the 131R-158V haplotype in lupus nephritis (30.4%) vs. lupus non-nephritis (15.8%) was noticed. Surprisingly, in spite of the high frequency of the FCGR2B-232T allele in our population, our study did not highlight any association of this allele either with SLE or lupus nephritis (a severe and frequent form of SLE). CD72-Hap1, which has been shown to confer resistance to SLE against T232 allele, was not enhanced in the control group. Our results emphasize an association between FCGR2A-131R and lupus nephritis with a distinctive FCGR polymorphism distribution in an indigenous African Caribbean population, confirming the important variation in the FCGR locus depending on ethnic origin. Full article

Background/Objectives: Refractory community-acquired pneumonia (r-CAP) has become a thorny issue in clinical practice, especially after the COVID-19 pandemic, even in immunocompetent patients, as conventionally defined. In this study, we aimed to identify the risk factors for immunocompetent patients with r-CAP. Methods: This was a single-center retrospective study. In total, we collected clinical data from 82 patients with r-CAP in whom the first-line antibiotic therapy failed and 82 patients with general CAP (g-CAP) who recovered with first-line antibiotics, matched at a ratio of 1:1, admitted to Beijing Shijitan Hospital, Capital Medical University, from 1 January 2022, to 31 December 2023. The differences between the two groups (clinical characteristics, peripheral blood cell count, lymphocyte subsets, and regular laboratory indicators) were analyzed using paired t, paired Wilcoxon, Chi-square, or Fisher’s exact tests, and univariate and multivariate logistics regression analyses were conducted to identify the independent risk factors. A model for predicting indicators with statistical significance was established and proved with the receiver operating characteristic (ROC) curve. Results: Warm season, a history of chronic obstructive pulmonary disease, longer time from onset to admission (T_O-A), higher percentages of CD4⁺ T, CD8⁺ T, and double-negative T (DNT) lymphocytes, as well as higher levels of C-reactive protein (CRP), low-density lipoprotein cholesterin (LDL-C), serum sodium ion (Na⁺), and free-calcium ion (FCa²⁺) were regarded as independent risk factors, while T lymphocyte percentage (T%) and total cholesterol (TC) were identified as protective factors. The combined multivariate model using all the above factors proved to be sensitive and specific (AUC = 0.8711, p < 0.0001, R² = 0.4235), and thus better than the respective univariate models. Conclusions: Increased CD4⁺ T%Lym, CD8⁺ T%Lym, and DNT%Lym, warm season, a history of COPD, longer T_O-A, and increased levers of CRP, LDL-C, Na⁺, and FCa²⁺ potentially cause CAP to be refractory, while the T lymphocyte count, namely, the overall cellular immunity, was impaired in r-CAP patients, and increased TC levels could be beneficial to pneumonia recovery. Full article

The ongoing global threat posed by the influenza A virus, exacerbated by antigenic drift and the emergence of antiviral resistance, accentuates the urgent need for innovative therapeutic strategies. Through molecular docking, this study revealed that mangiferin has a strong binding affinity for the active site of the neuraminidase (NA) protein of influenza virus A(H1N1)pdm09, with a binding energy of −8.1 kcal/mol. In vitro assays confirmed a dose-dependent inhibition of NA, with an IC₅₀ of 88.65 μM, and minimal cytotoxicity, as indicated by a CC₅₀ of 328.1 μM in MDCK cells. In murine models, the administration of mangiferin at a dosage of 25 mg/kg significantly mitigated weight loss, decreased viral loads in nasal turbinates and lungs by over 1 log10 TCID₅₀, and enhanced survival rates from 0% in control groups to 20% in mangiferin-treated group at 14 days post-infection. In addition, mangiferin was found to modulate host immune responses by simultaneously inhibiting pro-inflammatory cytokines, IL-6 and TNF-α, and upregulating the expression of anti-inflammatory IL-10 and antiviral IFN-γ, thus mitigating infection-induced inflammation. Our findings elucidate the dual mechanism of mangiferin involving the direct inhibition of NA and immunomodulation, thereby providing experimental evidence for exploring dual-mechanism-based anti-influenza strategies against resistant strains of influenza. Full article

Background/Objectives: There is a need for effective seasonal influenza virus vaccines that provide broad and long-lasting protection against influenza virus infections. Methods: In this study, next-generation influenza hemagglutinin (HA) and neuraminidase (NA) vaccine candidates designed using the computationally optimized broadly reactive antigen (COBRA) methodology were formulated with the TLR9 agonist, CpG 1018. These adjuvanted COBRA HA/NA vaccines were administered intramuscularly or intranasally to mice with pre-existing anti-influenza immunity or immunologically naïve mice. Results: Mice with pre-existing immune responses to historical influenza virus strains vaccinated intranasal (IN) with COBRA HA/NA vaccines adjuvanted with CpG 1018 had enhanced IgG titers in their bronchoalveolar lavages (BALF) compared to unadjuvanted vaccines. These mice also had increased serum IgG titers that were like antibody titers observed in mice that were vaccinated intramuscularly. Mice that were vaccinated intranasally with this adjuvanted vaccine also had antibodies with significantly higher hemagglutination inhibition activity against a broad range of H1N1 and H3N2 influenza viruses and more HA and NA specific antibody-secreting cells compared to unadjuvanted vaccine. Following the H1N1 influenza virus challenge, pre-immune mice that were vaccinated with the COBRA HA/NA vaccine with CpG 1018 were protected from morbidity and mortality and had no detectable viral lung titers. Conclusions: Overall, CpG 1018 adjuvanted COBRA HA/NA elicited enhanced protective antibodies compared to the unadjuvanted vaccine against several drifted H1N1 and H3N2 influenza viruses in pre-immune mice that were either intramuscularly or intranasally vaccinated with a balanced Th1/Th2 immune response. Full article

Excess selenium (Se) can cause a variety of toxic effects in aquatic animals. However, there is currently a lack of comprehensive studies about the toxicity effects of Se in culture water on shrimp. Based on the 96 h acute toxicity test, which confirmed the 96 h LC₅₀ of Se (Na₂SeO₃) for Litopenaeus vannamei as 2.69 mg/L, L. vannamei (7.25 ± 0.05 g) were divided into three groups (named CON, S1 and S2) and exposed to Se at concentrations of 0, 0.0269 (0.01 × 96 h LC₅₀), and 0.269 (0.1 × 96 h LC₅₀) mg/L in the water for 72 h, respectively. The toxic effects of Se exposure on L. vannamei were evaluated based on histopathology, oxidative stress, immunity, apoptosis, transcriptional responses, and intestinal microbiota. Results demonstrated that Se exposure induced structural damage to the hepatopancreas of L. vannamei, including hepatocyte vacuolation and necrosis. Compared to the CON group, serum Caspase-3 activity significantly increased, while Bcl-2 activity markedly decreased in the S1 and S2 groups (p < 0.05). No significant differences in Bax activity were observed among groups (p > 0.05). ROS content, as well as activities of SOD, PO, GSH-PX, LYS, AKP, and ACP, exhibited an upward trend under Se exposure (p < 0.05). However, MDA levels showed no significant intergroup differences (p > 0.05). Hemocyte transcriptomic analysis revealed 2103 differentially expressed genes (DEGs) (1294 upregulated, 809 downregulated) in the S2 group compared to CON. GO enrichment indicated significant enrichment of DEGs in cellular processes, binding, and cell components. KEGG pathway analysis highlighted prominent enrichment in ribosome biogenesis in eukaryotes, lysosome, cell cycle, and pancreatic secretion pathways. Intestinal microbiota analysis showed that the Shannon, Simpson, and Pielou indices in the S2 group were significantly lower than those in the CON group (p < 0.05). The relative abundance of Vibrio and Acinetobacter increased significantly in the S2 group, while Enterococcus and Pseudomonas decreased markedly (p < 0.05). In conclusion, Se exposure triggered elevated immune enzyme activities, induced oxidative damage and apoptosis, transcriptional level metabolic disorders, and disrupted intestinal microbiota structure in L. vannamei. Full article

Calcium (Ca²⁺) signaling is a fundamental regulatory mechanism controlling essential processes in the endothelium, vascular smooth muscle cells (VSMCs), and the extracellular matrix (ECM), including maintaining the endothelial barrier, modulation of vascular tone, and vascular remodeling. Cytosolic free Ca²⁺ concentration is tightly regulated by a balance between Ca²⁺ mobilization mechanisms, including Ca²⁺ release from the intracellular stores in the sarcoplasmic/endoplasmic reticulum and Ca²⁺ entry via voltage-dependent, transient-receptor potential, and store-operated Ca²⁺ channels, and Ca²⁺ elimination pathways including Ca²⁺ extrusion by the plasma membrane Ca²⁺-ATPase and Na⁺/Ca²⁺ exchanger and Ca²⁺ re-uptake by the sarco(endo)plasmic reticulum Ca²⁺-ATPase and the mitochondria. Some cell membranes/organelles are multifunctional and have both Ca²⁺ mobilization and Ca²⁺ removal pathways. Also, the individual Ca²⁺ handling pathways could be integrated to function in a regenerative, capacitative, cooperative, bidirectional, or reciprocal feed-forward or feed-back manner. Disruption of these pathways causes dysregulation of the Ca²⁺ signaling dynamics and leads to pathological cardiovascular conditions such as hypertension, coronary artery disease, atherosclerosis, and vascular calcification. In the endothelium, dysregulated Ca²⁺ signaling impairs nitric oxide production, reduces vasodilatory capacity, and increases vascular permeability. In VSMCs, Ca²⁺-dependent phosphorylation of the myosin light chain and Ca²⁺ sensitization by protein kinase-C (PKC) and Rho-kinase (ROCK) increase vascular tone and could lead to increased blood pressure and hypertension. Ca²⁺ activation of matrix metalloproteinases causes collagen/elastin imbalance and promotes vascular remodeling. Ca²⁺-dependent immune cell activation, leukocyte infiltration, and cholesterol accumulation by macrophages promote foam cell formation and atherosclerotic plaque progression. Chronic increases in VSMCs Ca²⁺ promote phenotypic switching to mesenchymal cells and osteogenic transformation and thereby accelerate vascular calcification and plaque instability. Emerging therapeutic strategies targeting these Ca²⁺-dependent mechanisms, including Ca²⁺ channel blockers and PKC and ROCK inhibitors, hold promise for restoring Ca²⁺ homeostasis and mitigating vascular disease progression. Full article

Cardiac glycosides (CGs), a class of plant- and animal-derived compounds historically used to treat heart failure, have garnered renewed interest for their diverse pharmacological properties beyond Na⁺/K⁺-ATPase (NKA) inhibition. Recent studies reveal that CGs modulate key signaling pathways—such as NF-κB, PI3K/Akt, JAK/STAT, and MAPK—affecting processes central to cancer, viral infections, immune regulation, and neurodegeneration. In cancer, CGs induce multiple forms of regulated cell death, including apoptosis, ferroptosis, pyroptosis, and immunogenic cell death, while also inhibiting angiogenesis, epithelial–mesenchymal transition, and cell cycle progression. They demonstrate broad-spectrum antiviral activity by disrupting viral entry, replication, and mRNA processing in viruses such as HSV, HIV, influenza, and SARS-CoV-2. Immunologically, CGs regulate Th17 differentiation via RORγ signaling, although both inhibitory and agonistic effects have been reported. In the nervous system, CGs modulate neuroinflammation, support synaptic plasticity, and improve cognitive function in models of Alzheimer’s disease, epilepsy, and multiple sclerosis. Despite their therapeutic potential, clinical translation is hindered by narrow therapeutic indices and systemic toxicity. Advances in drug design and nanocarrier-based delivery are critical to unlocking CGs’ full potential as multi-target agents for complex diseases. This review synthesizes the current knowledge on the emerging roles of CGs and highlights strategies for their safe and effective repurposing. Full article

Gibel carp (Carassius auratus gibelio) were hypoxia stressed for 12 h after an 8-week FPR nutrient-enriched feeding experiment, which was to evaluate the role of FPR in hypoxic stress in gibel carp (Carassius auratus gibelio). The dissolved oxygen was reduced to a range of 0.6 ± 0.2 mg/L. Results showed that FPR supplementation could maintain the osmotic pressure equilibrium by improving the ion concentrations of plasma including Na⁺, Ca⁺ and K⁺, and Na⁺/K⁺-ATPase activity of liver. FPR supplementation could effectively enhance the antioxidant capacity by improving the levels of GPX, SOD, CAT, and GSH, and reduce the level of MDA. FPR supplementation could improve the core gene expressions of Nrf2 signalling pathway including nrf2, sod, ho-1, gpx, and cat. The high levels of FPR supplementation (0.04%) might had a negative effect on immunity. FPR supplementation could improve the expression levels of HIF-1 signalling pathway-related genes to adapt to hypoxia condition including hif-1α, epo, angpt1, vegf, et1, and tfr-1. These results also were supported by higher SR and number of gill mitochondria in FPR supplementation. In general, the appropriate FPR supplementation was 0.01% based on the results of this study and economic cost, which could heighten hypoxic adaptation and SR. Full article

Recent evidence suggests a high-sodium microenvironment in breast tumors. However, the exact role of this high-sodium microenvironment on tumorigenesis is unknown. Salt (sodium chloride, NaCl) is a well-known inflammatory molecule playing a significant role in various chronic ailments like cardiovascular and autoimmune diseases. Importantly, chronic inflammation is recognized as one of the major hallmarks of carcinogenesis. Breast cancer cell culture-based studies demonstrated that high-salt (HS) treatment (Δ35–50 mM NaCl) induced cancer cell proliferation. However, preclinical murine research showed reduced tumor progression kinetics in mice fed a short-term HS diet (4% NaCl diet, 0–2 weeks prior to the injection of tumor cells). Molecular studies demonstrated that the short-term HS diet induced the inflammatory activation of naïve CD4+ T cells to the Th17/Th1 anti-tumor phenotype. As human health-related adverse outcomes from HS diets usually occur as a consequence of prolonged HS intake over a period of several years, we have developed a novel chronic HS dietary murine tumor model. In this model, tumor cells are sequentially passaged (four cycles) in vivo under high-salt conditions, and tumor kinetics were analyzed in the passage-4 mice. These studies demonstrated enhanced tumor progression (pro-tumor) under chronic HS dietary conditions through the activation of tumor-initiating stem cells, along with the exhaustion of immune cells. Based on the, apparently paradoxical, evidence, we propose a comprehensive unifying hypothesis to elucidate the complex role of a high-sodium microenvironment towards tumor immune sculpting. This understanding will enable novel drug repositioning strategies, the development of unique ion channel-based anti-cancer therapeutics and promote low-salt diet intake in breast cancer patients on immunotherapy. Full article