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Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival.

Targeting the site of infection is a promising strategy for improving vaccine effectivity. To date, licensed COVID-19 vaccines have been administered intramuscularly despite the fact that SARS-CoV-2 is a respiratory virus. Here, we aim to induce local protective mucosal immune responses with an inhaled subunit vaccine candidate, ISR52, based on the SARS-CoV-2 Spike S1 protein. When tested in a lethal challenge hACE2 transgenic SARS-CoV-2 mouse model, intranasal and intratracheal administration of ISR52 provided superior protection against severe infection, compared to the subcutaneous injection of the vaccine. Interestingly for a protein-based vaccine, inhaled ISR52 elicited both CD4 and CD8 T-cell Spike-specific responses that were maintained for at least 6 months in wild-type mice. Induced IgG and IgA responses cross-reacting with several SARS- CoV-2 variants of concern were detected in the lung and in serum and protected animals displayed neutralizing antibodies. Based on our results, we are developing ISR52 as a dry powder formulation for inhalation, that does not require cold-chain distribution or the use of needle administration, for evaluation in a Phase I/II clinical trial.

Allergic rhinitis (AR) and non-allergic rhinitis (NAR) are the main forms of chronic rhinitis with distinct pathogenesis. Endotype analysis based on nasal mucosal immune markers may facilitate precision medicine. To compare inflammatory profiles and identify endotypes in AR and NAR through local immune marker detection and correlation analysis. This retrospective study enrolled chronic rhinitis patients (January 2023-June 2025) divided into three groups: AR group [ARG, n=40, positive skin prick test and/or serum specific IgE (sIgE)], NAR group (NARG, n=40, negative allergy tests), and control group (CG, n=20). Primary measures: nasal eosinophil (EOS) and neutrophil (NEU) counts, sIgE and eosinophil cationic protein (ECP), Th2 cytokines, NEU-related mediators, and immune cell subsets. ARG showed significantly higher EOS count, sIgE, ECP, interleukin-5 (IL-5), interleukin-13 (IL-13), and EOS% than NARG and CG. NARG exhibited significantly higher NEU count, interleukin-8 (IL-8), interleukin-1β (IL-1β), and NEU% (  < 0.01). Correlation analysis revealed moderate to strong positive correlations among Th2 markers in ARG and among NEU markers in NARG, with ECP also correlated to EOS in NARG (all  < 0.05). AR exhibits a Th2-dominant inflammatory network involving eosinophils, IgE, and Th2 cytokines rather than eosinophils alone, while NAR displays a NEU-mediated pattern with a subset showing eosinophilic activation. Multi-marker detection in nasal secretions effectively differentiates inflammatory endotypes in chronic rhinitis. This study identified a synergistic Th2 network in AR and a NEU-dominant pattern in NAR via nasal secretion analysis, providing evidence for endotype identification and precision therapy.

Background/Objectives: Persistent high-risk human papillomavirus (HPV) infections are the leading cause of cervical cancer. Developing evidence suggests that the cervicovaginal microbiome plays a significant role in modulating HPV persistence and progression to cervical neoplasia. This review synthesizes the current knowledge on the interplay between the cervicovaginal microbiome and local immunity in HPV infections, emphasizing microbial diversity, immune responses, and potential therapeutic implications. Methods: A thorough review of the literature was performed using Embase, PubMed, Scopus, and Google Scholar, encompassing studies published between 2000 and 2024. Studies examining the composition of the microbiome, immune responses, and HPV-related outcomes were evaluated and synthesized into a comprehensive review. Results: A Lactobacillus-dominant microbiome, particularly with L. crispatus, creates a protective environment through lactic acid production, maintenance of low pH, and anti-inflammatory immune modulation, facilitating HPV clearance. Dysbiosis, often characterized by a dominance of L. iners and overgrowth of anaerobic bacteria, fosters chronic inflammation, cytokine imbalance, and a microenvironment conducive to HPV persistence and progression. Hormonal changes and menopause exacerbate these microbial shifts, increasing the risk of cervical lesions. Studies suggest that cytokine profiles and antimicrobial peptides significantly influence local immune responses, further modulating infection outcomes. Conclusions: The cervicovaginal microbiome is a critical determinant in HPV infection outcomes, with therapeutic potential for modulating the microbiome to enhance immune responses and prevent cervical cancer. Personalized microbiome-targeted therapies may offer a novel avenue for managing HPV and reducing cervical cancer incidence.

Plants are continuously exposed to pathogen challenges. To defend themselves, plants have developed sophisticated innate and induced immune responses. The recognition of invading pathogens by membrane-localized or intracellular receptors triggers a local immune response, but plants often also establish a systemic immunity throughout the entire plant body to confer broad-spectrum and long-lasting resistance to secondary infections. Both the local and systemic immune responses are regulated by several phytohormones, including jasmonic acid, ethylene, and salicylic acid, which induce genome-wide transcriptional reprogramming to elicit effective immune responses. During this transcriptional reprogramming, epigenetic mechanisms are engaged to modulate chromatin structure and the accessibility of cis -elements to transcription factors. In this review, we first describe how the model plant Arabidopsis thaliana recognizes invading pathogens to trigger local and systemic immune responses. Next, we describe how phytohormones mediate transcriptional responses, establishing immunity. Finally, we review recent findings in the epigenetic aspect of immunity in Arabidopsis.

Despite the great interest in the development of a vaccine against African swine fever (ASF) in wild boar, the immunological mechanisms that induce animal protection are still unknown. For this purpose, tertiary lymphoid organs (TLOs) of wild boar were characterised and compared with mucosa-associated lymphoid tissues (MALTs) by histopathology, histomorphometry and immunohistochemistry (CD3, CD79, PAX5, LYVE1, fibronectin). In addition, real-time polymerase chain reaction (qPCR) and immunohistochemistry (p72) were used to evaluate the presence of ASF virus (ASFV) in blood and tissues samples, respectively. TLOs were observed in animals infected with a low-virulent ASFV isolate (LVI), animals co-infected with low and high-virulent ASFV isolates (LVI-HVI) and animals infected only with the high virulence isolate (HVI). TLOs in LVI and LVI-HVI groups were located adjacent to the mucosa and presented a similar structure to MALT. Immunoexpresion of p72 observed in the inflammatory cells adjacent to TLOs/MALTs confirmed its development and reactivity generated by ASF attenuated isolates. Immunohistochemical evaluation, based on cellular composition (T and B lymphocytes), and histomorphometrical study revealed a more pronounced maturation of TLOs/MALTs in the LVI-HVI group. It is currently unclear whether these formations play a protective role by contributing to local immunity in chronic inflammatory diseases. However, the structural similarities between TLOs and MALTs and the location of TLOs close to the mucosa suggest that they may perform a similar function, facilitating a local protective response. Nevertheless, further investigations are warranted to assess the cellular and humoral dynamics of these lymphoid organs induced by attenuated isolates.

Hostile microenvironment produced by abnormal blood vessels, which is characterized by hypoxia, low pH value and increasing interstitial fluid pressure, would facilitate tumor progression, metastasis, immunosuppression and anticancer treatments resistance. These abnormalities are the result of the imbalance of pro-angiogenic and anti-angiogenic factors (such as VEGF and angiopoietin 2, ANG2). Prudent use of anti-angiogenesis drugs would normalize these aberrant tumor vessels, resulting in a transient window of vessel normalization. In addition, use of cancer immunotherapy including immune checkpoint blockers when vessel normalization is achieved brings better outcomes. In this review, we sum up the advances in the field of understanding and application of the concept of tumor vessels normalization window to treat cancer. Moreover, we also outline some challenges and opportunities ahead to optimize the combination of anti-angiogenic agents and immunotherapy, leading to improve patients’ outcomes.

As a newly discovered cytokine, interleukin 9 was initially considered a T-lymphocyte growth factor. Interleukin 9 affects target cells by binding to a member of the γc-family of receptors and is involved in inflammation, autoimmune diseases, and other ailments. In recent years, mounting evidence reveals that interleukin 9 exerts antitumor effects, which has attracted considerable attention. Many previous studies were performed in vivo by establishing a mouse model of melanoma. Here, interleukin 9 protein and messenger RNA expression levels were both low in colon carcinoma tissue specimens, as assessed by immunohistochemistry and quantitative real-time polymerase chain reaction. In addition, interleukin 9 expression in these samples was correlated with TNM staging, Dukes staging, lymph node metastasis, and good prognosis, but not with gender, age, tumor size, tumor differentiation, and hepatic metastasis. In vivo, by establishing a mouse subcutaneous allograft model, we found that interleukin 9 overexpression inhibited tumor growth and resulted in longer survival time. Then, antitumor immune responses were increased by interleukin 9 as demonstrated by flow cytometry. Furthermore, interleukin 9 was shown to exert antitumor effects by regulating T-cell function and killing tumor cells in the tumor microenvironment. Overall, this study revealed that interleukin 9 exerts robust antitumor effects in colon cancer and transforms the tumor microenvironment in vivo.

The study evaluated the patterns of local innate immune response in bronchoalveolar lavage fluid (BALF) cells of pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV) alone or co-infected with swine influenza virus (SIV). The study was performed on 26 seven-week-old pigs in three groups: PRRSV-infected (n = 11), PRRSV and SIV-infected (n = 11), and control (n = 4). BALF was collected post euthanasia at 2 and 4 dpi (three piglets per inoculated group) and at 21 dpi (all remaining pigs). Expression of IFN-α, IFN-γ, IL-1β, IL-6, IL-8, and IL-10 mRNA was quantified in BALF cells. PRRSV RNA was quantified in BALF samples using a commercial real-time RT-PCR kit. The three cytokines IFN-α, IFN-γ, and IL-1β presented significant expression changes in all experimental pigs. In PRRSV-infected animals IL-8 also did, but in co-infected subjects IL-6 and IL-10 were the additional upregulated cytokines. The highest number of differentially expressed genes was observed at 4 dpi, and significant differences in cytokine gene expression did not occur between the experimental groups at any other time point. The mean PRRSV load in the BALF of PRRSV-infected pigs was higher than that of co-infected pigs at each time point, having statistical significance only at 4 dpi. The results of the study indicate that infection with PRRSV alone as well as with SIV interferes with innate and adaptive immune response in the infected host. They also showed that co-infection demonstrates additive effects on IL-6 and IL-10 mRNA expression levels.