Search Results (7,683)

Immunotherapy has transformed cancer treatment; however, clinical benefit remains limited to a subset of patients, underscoring the need for robust biomarkers that capture tumor-immune interactions across cancer types. In this study, we performed a comprehensive pan-cancer, multi-omics characterization of the immune checkpoint–related molecules CD70, CD80, and TIGIT to evaluate their diagnostic, prognostic, and immunological relevance. Using integrative analyses of transcriptomic, epigenomic, genomic, pharmacogenomic, and single-cell RNA-sequencing data from The Cancer Genome Atlas and complementary resources, we assessed expression patterns, DNA methylation, somatic mutations, copy number alterations, immune infiltration, tumor stemness, and drug sensitivity. CD70, CD80, and TIGIT were broadly dysregulated across multiple malignancies, with coordinated overexpression particularly evident in kidney renal clear-cell carcinoma. Elevated expression of these immune checkpoints was associated with advanced tumor stage, aggressive molecular subtypes, and unfavorable survival outcomes in selected cancers, including uveal melanoma and renal malignancies. Functional analyses revealed significant associations between checkpoint expression and key oncogenic pathways, including epithelial–mesenchymal transition, apoptosis, and hormone receptor signaling, suggesting links with tumor progression and immune activation states. Immune deconvolution analyses indicated that TIGIT expression is associated with a T-cell–inflamed microenvironment and reduced neutrophil infiltration, while CD80 exhibited methylation-dependent associations with immune cell composition. Genomic and epigenetic alterations were found to correlate with checkpoint expression patterns and immune phenotypes across tumor types. Pharmacogenomic profiling identified associations between checkpoint expression and sensitivity to multiple anticancer agents; however, these findings are based on cell line datasets and should be considered predictive. Single-cell transcriptomic analyses further resolved cell-type–specific expression patterns, distinguishing tumor-intrinsic from immune-restricted expression profiles. Collectively, our findings establish CD70, CD80, and TIGIT as integrative biomarkers of tumor progression, immune contexture, and therapeutic response, providing a rationale for their clinical exploitation in precision immuno-oncology. Full article

Background/Objectives: Despite widespread antiretroviral therapy (ART) use, whether the expected transition from AIDS-defining to non-AIDS-defining cancers has occurred in settings with persistent late HIV presentation remains unclear. We examined long-term cancer patterns, determinants, and survival outcomes in a large HIV cohort. Methods: This retrospective, single-center cohort included 1419 people living with HIV followed between 2006 and 2024. Patients who developed malignancy were classified as AIDS-defining cancers (ADC) or non-AIDS-defining cancers (NADC). Immuno-virological parameters were assessed at HIV and cancer diagnosis. Survival was analyzed using Kaplan–Meier methods, and predictors of mortality were evaluated using Cox proportional hazards regression. Determinants of ADC development were assessed using multivariable logistic regression. Temporal changes were evaluated by trend analysis. Results: Sixty-six patients (4.6%) developed malignancy (31 ADC, 35 NADC). Late HIV presentation was common, with 72.7% having CD4+ T-lymphocyte counts < 350 cells/mm³ at cancer diagnosis, particularly among ADC cases. Most ADCs (93.5%) occurred within 24 months of HIV diagnosis. Overall survival did not differ between ADC and NADC groups (log-rank p = 0.14). Although mortality declined after 2015, temporal changes in ADC and NADC proportions did not reach statistical significance (p = 0.14). In Cox regression analysis, viral suppression before death or last follow-up was independently associated with lower mortality risk (HR 0.12; 95% CI 0.05–0.31). Lower CD4+ T-lymphocyte counts were associated with ADC development, and a CD4+ T-lymphocyte threshold of 295 cells/mm³ showed good discriminative performance (AUC = 0.83), although this cutoff should be interpreted cautiously due to the lack of external validation. Conclusions: In this long-term cohort from Türkiye, a clear epidemiological transition from ADC to NADC could not be demonstrated. The cancer spectrum remained strongly influenced by late HIV presentation and advanced immunodeficiency. Sustained viral suppression was independently associated with lower mortality risk, supporting the importance of early HIV diagnosis, timely ART initiation, and sustained virological control. Full article

Immune checkpoint inhibitors (ICIs) show promise in cancer but have limited efficacy in ovarian cancer. This study compared combinations of the PD-1/PD-L1 inhibitor with anti-LAG-3, anti-TIM-3, or anti-CTLA-4 to identify the most effective regimen by assessing T-cell CD8/CD4 ratios and cytokine production. T cells isolated from ovarian cancer tissues (mean 3.8 × 10⁸ cells) were stimulated and treated with the PD-1/PD-L1 inhibitor alone or combined with anti-LAG-3, anti-TIM-3, or anti-CTLA-4. Flow cytometry measured CD8/CD4 expression; ELISAs quantified TNF-α, IL-6, and IFN-γ. Anti-PD-1 monotherapy produced no significant change in CD8/CD4 ratio (1.36 ± 0.43 vs. 1.41 ± 0.36) or cytokine levels. Combination therapy with PD-1/PD-L1 inhibitor + anti-CTLA-4 induced the largest increase in CD8/CD4 ratio (3.69 ± 1.33, p < 0.001) compared with PD-1/PD-L1 inhibitor alone; increases were smaller for PD-1/PD-L1 inhibitor + anti-LAG-3 (2.11 ± 0.63, p = 0.009) and PD-1/PD-L1 inhibitor + anti-TIM-3 (1.87 ± 0.48, p = 0.026). TNF-α rose significantly only with PD-1/PD-L1 inhibitor + anti-CTLA-4 (106.69 ± 45.42 pg/mL, p = 0.008), not with PD-1/PD-L1 inhibitor + anti-LAG-3 (72.46 ± 31.79 pg/mL, p = 0.231) or PD-1/PD-L1 inhibitor + anti-TIM-3 (82.06 ± 33.63 pg/mL, p = 0.074). IFN-γ increase was greater with PD-1/PD-L1 inhibitor + anti-CTLA-4 than with PD-1/PD-L1 inhibitor + anti-LAG-3 (p = 0.026). In conclusion, dual PD-1/PD-L1 and CTLA-4 blockade induced concomitant increases in T-cell CD8/CD4 proportions and cytokine levels compared to monotherapy or alternative ICI pairings. These descriptive ex vivo observations offer preliminary evidence of altered immune profiles, highlighting this combination as a candidate for further functional validation. Full article

Background: The tumor immune microenvironment, particularly the role of cytotoxic CD8+ T lymphocytes, is crucial in cancer progression but remains poorly understood in pituitary neuroendocrine tumors (PitNETs). The significance of CD8+ cell infiltration varies across PitNET subtypes, suggesting a complex interplay with tumor cell lineage. This study aimed to characterize the distribution of CD8+ tumor-infiltrating lymphocytes across different PitNET subtypes defined by the current WHO classification and to explore their association with clinicopathological features. Methods: We conducted a retrospective study on 40 surgically resected PitNETs. All cases were classified based on immunohistochemical expression of pituitary hormones and lineage-specific transcription factors (PIT-1, TPIT, SF-1). CD8+ lymphocyte density was quantified using immunohistochemistry and calculated as cells/mm². Exploratory statistical analysis was performed based on non-parametric tests to compare CD8+ cell density across tumor subtypes and with parameters like tumor size, invasiveness (Knosp grade), and proliferation index (Ki-67). Findings are to be treated as observational trends. Results: The highest density of CD8+ lymphocytes was observed in plurihormonal PIT-1-positive tumors [17.61 cells/mm² (IQR: 17.61–60.36)], followed by somatotroph [13.2 (6.6–15.72)] and mammosomatotroph [13.83 (0–21.38)] tumors. A difference in CD8+ density was found between PIT-1-positive and PIT-1-negative tumors (n1 = 34, n2 = 6, U = 49.5, p_exact = 0.050, r = 0.33); the medium effect size indicates a possible lineage-related trend. Another difference was observed between SF-1-positive and SF-1-negative tumors (p = 0.025), with SF-1 lineage tumors showing the lowest infiltration. No correlations were found between CD8+ density and tumor size, Knosp grade, or Ki-67 index. Conclusions: The distribution of intratumoral CD8+ T lymphocytes in PitNETs is highly heterogeneous and appears to be strongly dictated by the transcription factor-defined tumor lineage rather than by traditional clinicopathological markers of aggressiveness. PIT-1 lineage tumors harbor a more active immune microenvironment, while SF-1 lineage tumors are relatively ‘immune-poor’. These findings highlight the immunological diversity of PitNETs and support further investigation of the tumor immune landscape. Collaborative multi-institutional studies are required to validate these trends. Full article

Per- and polyfluoroalkyl substances (PFAS) are persistent, chemically stable compounds widely used in daily life. Perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), and perfluorooctanesulfonic acid (PFOS) were identified as the most relevant PFAS due to their prevalence and toxicity. This study aimed to investigate the immunotoxic mechanisms of a mixture of these PFAS using an in silico approach. Comparative Toxicogenomic Database (CTD), GeneMANIA, CytoHubba (Cytoscape), ToppGene Suite, and Metascape were used for the analysis. A total of 65 immune-related genes were identified as common to all four PFAS, with IFNG, TNF, IL1B, IL6, TYK2, CD3E, CASP8, VAV1, ARHGAP4, and CARD11 emerging as key hub genes. CTD phenotype analysis indicated immune dysregulation, with decreased humoral and adaptive immune responses in humans and tissue-specific modulation of B- and T-cell activity in mice, while no immune-related phenotypes were observed for PFNA. Network analysis identified functional modules associated with apoptotic and immune signaling, endothelial cell migration and angiogenesis, and shared inflammatory and viral response pathways. Disease enrichment analysis associated PFAS with autoimmune disorders (rheumatoid arthritis, asthma), metabolic conditions, and cardiovascular diseases (experimental diabetes, hypertensive disease). These results highlight PFAS involvement in immune modulation, cytokine signaling, and disease susceptibility. Full article

Cross-presentation of exogenous antigens by dendritic cells (DCs) relies on the cytosolic pathway, enabling proteasomal processing and subsequent loading of antigenic peptides onto major histocompatibility complex class I (MHC-I) molecules. Although this pathway is central to CD8⁺ T-cell activation, the molecular mechanisms that regulate intracellular antigen processing and redistribution during cross-presentation remain incompletely defined. In this study, we investigated the contribution of the large-pore channel Pannexin-1 (Panx1) to antigen handling during cross-presentation. Using confocal microscopy and quantitative image analysis in granulocyte–macrophage colony-stimulating factor/interleukin-4 (GM-CSF/IL-4)-derived inflammatory bone marrow-derived dendritic cell (BMDC)-like cellsexposed to ovalbumin (OVA)–Alexa Fluor 488, we observed time-dependent changes in intracellular antigen distribution that were altered upon pharmacological inhibition of Panx1 with the blocking peptide 10Panx1. In parallel, functional assays revealed that Panx1 inhibition significantly reduced SIINFEKL peptide-dependentactivation of B3Z CD8⁺ T-cell hybridomas following pulsing with full-length OVA. Similar effects were observed in the cross-presentation-competent MUTU1940 dendritic cell line. Importantly, Panx1 inhibition did not significantly affect dendritic-cell viability or LPS-induced activation under the experimental conditions tested. In contrast, pharmacological inhibition or genetic deficiency of P2X7 receptor (P2X7) did not produce comparable reductions in cross-presentation, and combined inhibition did not result in additive effects under the experimental conditions tested. Together, these findings provide functional evidence supporting a role for Panx1 in regulating intracellular antigen redistribution associated with cross-presentation. While not establishing direct genetic causality, our data identify Panx1 as a modulatory component influencing antigen-processing events that culminate in CD8⁺ T-cell activation, thereby expanding the current framework of intracellular antigen-processing mechanisms involved in dendritic-cell-mediated cross-presentation. Full article

Background: Toxoplasmosis is a prevalent zoonotic disease worldwide, affecting approximately one-third of the global human population. Primary infection with Toxoplasma gondii during pregnancy can induce miscarriage or congenital infection, leading to irreversible damage to the foetus. Moreover, reactivation of T. gondii infection in immunosuppressed individuals can result in fatal outcomes. No vaccine exists to prevent human disease caused by this parasite. Thus, a vaccine that could induce complete and lasting protection against human toxoplasmosis is an unmet need. Method: In this work, BALB/cByJ mice were intranasally immunised with a subunit vaccine consisting of T. gondii membrane proteins (TGMP) from the T. gondii Me49 strain plus CpG-oligodeoxynucleotide adjuvant (CpG). Antibody responses were analysed by ELISA, while T-cell responses were evaluated by flow cytometry. The immunogenic proteins present in TGMP were identified by mass spectrometry, and parasite burden was quantified by qPCR. Result: The results showed raised TGMP-specific serum IgG and intestinal IgA antibody levels, and parasite-specific IFN-γ-producing CD4⁺ and CD8⁺ memory T cells. Dense granule proteins (GRA) 2 and 7, surface antigen (SAG)-related sequences 25, 29B, and 34A, microneme protein (MIC) 10, toxofilin, nascent polypeptide-associated complex (NAC) domain-containing protein, and NAC subunit beta were identified as immunogenic proteins. Mice immunised with TGMP+CpG were challenged with T. gondii tachyzoites and showed a significant reduction in the parasitic burden in the peritoneal exudate, spleen, and lungs, compared to mice sham-immunised with CpG alone. Conclusions: Altogether, these results indicate that mucosal immunisation with TGMP plus CpG adjuvant is worth exploring as a vaccination approach to prevent toxoplasmosis. Full article

Colorectal cancer (CRC) is intricately linked to gut microbiota dysbiosis and tryptophan (Trp) metabolic dysregulation. This study aimed to clarify the role and mechanisms of 20(S/R)-ginsenoside Rh1 in suppressing colorectal cancer through the regulation of gut microbiota and Trp metabolism. Azoxymethane/dextran sulfate sodium (AOM/DSS)was employed to induce a CRC mouse model, followed by treatment with 20(S/R)-ginsenoside Rh1 at 100 mg·kg⁻¹·day⁻¹ for 6 weeks. 20(S/R)-ginsenoside Rh1 significantly reduced the disease activity index (DAI) score, restored colon length, and decreased tumor count. 20(S/R)-Ginsenoside Rh1 ameliorated gut dysbiosis by increasing gut microbial diversity and elevating the prevalence of beneficial bacteria, including Lactobacillus, and stimulated the production of indole derivatives, including indole-3-propionic acid (IPA), indole-3-acetic acid (IAA), and indole-3-lactic acid (ILA) by enriching Trp -metabolizing bacteria such as Lactobacillus reuteri. These changes further activated the AhR/CYP1A1/IL-22 and PXR/TLR4 pathways, upregulated the expression of intestinal tight junction proteins, suppressed the secretion of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IFN-γ, and elevated the levels of the anti-inflammatory cytokine IL-10. Furthermore, 20(S/R)-ginsenoside Rh1 reduces the serum kynurenine (Kyn)/Trp ratio, downregulates the expression of forkhead box P3 (FoxP3), a marker of regulatory T (Treg) cells, and increases the number of CD8⁺ T cells by inhibiting the expression of indoleamine 2,3-dioxygenase 1 (IDO1) in colonic tissue. In conclusion, 20(S/R)-ginsenoside Rh1 showed potential anti-CRC activity, with our study observing links between its action and gut microbiota structure regulation, Trp metabolism modulation, AhR/PXR-mediated intestinal barrier activation, and IDO1-related immune suppression reversal. Full article

Local immune cell activation and vascular remodelling are characteristic pathogenic features of pulmonary arterial hypertension (PAH). HIV and schistosome infections have been individually associated with PAH. However, whether co-infection with these pathogens has a distinct impact on the development of pulmonary vascular disease remains poorly understood, partly due to the lack of experimental animal models. In a novel non-infectious model of HIV and Schistosoma pulmonary co-exposure based on lung embolisation of S. mansoni eggs in HIV-transgenic (HIV) mice, we previously reported exacerbated endothelial remodelling and dysfunction, along with increased pulmonary arterial pressure; which were associated with a unique profile of pro-inflammatory cytokines in the lung. In the present study, we used flow cytometric analysis of isolated lung leukocytes and immunofluorescence staining to characterise the pulmonary immune cell landscape associated with individual or combined exposure to HIV and schistosome. Compared with mice exposed to HIV (untreated HIV mice) or schistosome (egg-treated wild-type mice), co-exposed (egg-treated HIV mice) animals showed significantly increased numbers of interstitial and alveolar macrophages, patrolling-type monocytes, NKT and γδ T cells, and reduced CD8⁺ αβ T cells. Other lung immune cells, including inflammatory-type monocytes, eosinophils/neutrophils, dendritic cells, CD4⁺ αβ T cells, NK cells and B cells were not significantly affected in the co-exposure condition. Taken together, these results show for the first time that combined pulmonary exposure to HIV and Schistosoma, as it may occur in co-infected individuals, alters the local immune cell landscape in a manner distinct from that of individual exposure. Furthermore, these findings may contribute to a better understanding of the complex inflammatory processes involved in the pathogenesis of PAH, thereby supporting the development of therapies targeting pathogenic immune cells in pulmonary vascular disease associated with HIV and Schistosoma co-morbidity. Full article

CD22 is a critical inhibitory coreceptor predominantly expressed on the surface of B cells, playing a pivotal role in modulating B cell receptor (BCR) signaling and maintaining immune homeostasis. Its high B cell lineage specificity, rapid internalization capacity, and signal attenuation mediated by immunoreceptor tyrosine-based inhibitory motifs (ITIMs) render it an ideal therapeutic target for B cell-related pathologies. In recent years, CD22-targeted therapeutic strategies have demonstrated significant clinical breakthroughs in the treatment of hematological malignancies and autoimmune diseases. These strategies encompass immunotoxins, radioimmunoconjugates, antibody–drug conjugates (ADCs), bispecific antibodies, and chimeric antigen receptor (CAR) T cell therapy. Notably, while monotherapies have achieved high response rates, dual-targeting approaches (e.g., CD19/CD22 CAR-T) have further mitigated the risk of antigen escape and profoundly enhanced long-term durable efficacy. This review systematically summarizes the molecular mechanisms of CD22 and the latest clinical advancements in its targeted therapies. Furthermore, we highlight the promising translational potential of CD22-targeted strategies—particularly CAR-T cell therapy—from oncology to the management of autoimmune disorders, outlining future research priorities within this rapidly evolving field. Full article

Latently infected resting CD4+ T cells represent the principal barrier to HIV eradication. Their immunological quiescence renders them invisible to combination antiretroviral therapy (cART) and host immune surveillance, sustaining a reservoir that mandates lifelong treatment. The ‘shock and kill’ strategy seeks to reverse this latency using pharmacological latency-reversing agents (LRAs) so that immune effectors and cART can eliminate reactivated cells. In this narrative, structured review, we examine histone deacetylase inhibitors (HDACis) as LRAs from a medicinal chemistry perspective. The review places particular emphasis on structure–activity relationship (SAR), isoform selectivity, and the mechanistic basis of differential clinical performance, synthesizing evidence from preclinical, ex vivo, and clinical studies published between 2010 and 2026. Four structural classes of HDACis—hydroxamic acids, benzamides, cyclic depsipeptides, and short-chain fatty acids—differ substantially in isoform selectivity, potency, pharmacokinetics, and tolerability. No single agent has achieved statistically significant reservoir reduction in clinical trials, highlighting the apparent inadequacy of the ‘shock’ phase alone and suggesting a need for complementary ‘kill’ strategies. Rational design of HDACis informed by isoform-selective SAR, combined with emerging combination LRA strategies and immunological ‘kill’ components, represents a promising direction toward a functional HIV cure, though substantial translational hurdles remain. Full article

Background: Autism spectrum disorder (ASD) is associated with immune dysregulation in a subset of individuals, though findings remain heterogeneous and poorly defined, particularly regarding immune subtypes and metabolic context. Methods: We analyzed whole-blood microarray data from GSE18123 (GPL570: ASD n = 46, controls n = 19; GPL6244: ASD n = 68, controls n = 21) using an integrated immunometabolic framework. CD4⁺ T-cell transcriptional programs were used to assign dominant immune phenotypes (TH1, TH2, TH17, Tfh, FOXP3⁺ Treg, Tr1-like). Metabolic demand was quantified via the τ-axis; execution capacity was assessed using cytosolic and mitochondrial energy compensation ratios (CECR, MECR). Induction–execution mismatch was captured by three Gap metrics (Cytosolic, Warburg, Global). Functional validation correlated these metrics with transcriptional signatures of folate transport, one-carbon metabolism, receptor-mediated micronutrient uptake (LRP2–CUBN–AMN), cobalamin processing, and vitamin D activation across both platforms. Results: Six immunometabolic CD4⁺ subtypes were identified within ASD. τ-axis discrimination was strongest for Tr1-like (AUC = 0.811) and Tfh (AUC = 0.825) states, while TH17 profiles were indistinguishable from controls. Despite variation in metabolic demand, CECR and MECR remained relatively preserved, indicating decoupling between induction and execution capacity. Global Gap values were most negative in Tfh and TH1 states and positive in TH17 and controls. Negative Gap states showed coordinated suppression of ATP-intensive micronutrient acquisition pathways, including folate transport (FOLR1/2, SLC19A1), megalin–cubilin-mediated uptake (r ≈ 0.77–0.79), and vitamin D activation (CYP27B1). Intracellular cobalamin processing was upregulated in proportion to metabolic demand (r > 0.9). Findings were directionally replicated across both datasets. Conclusions: These data demonstrate that ASD exhibits structured immunometabolic heterogeneity characterized by subtype-specific demand–capacity imbalance. The Global Gap framework provides transcriptomic evidence of energetic deficit in Tfh- and Tr1-like-dominant states. Future clinical studies should incorporate subtype-stratified assessment of micronutrient status and metabolic execution capacity. Full article

The treatment of intracellular bacterial infections such as Chlamydia remains a significant clinical challenge due to rising antibiotic resistance and persistent, immunopathology-driven tissue damage. Macrophages are essential for host defense; they can originate from both tissue-resident precursors and circulating monocytes. During infection, macrophages at infected sites are largely derived from monocytes that migrate and differentiate there, where they phagocytose pathogens and orchestrate immune responses. The chemokine receptor CCR2 is a key regulator of this process, yet its role beyond monocyte trafficking is not fully understood. Previous studies have shown that CCR2 deficiency impairs monocyte mobilization and exacerbates disease during Chlamydia infection, shifting immune responses away from protective Th1 immunity toward pathological Th2 and Th17 polarization. Here, we investigate how CCR2 regulates macrophage function to balance protective Th1 versus pathological Th2/Th17 immunity during Chlamydia respiratory infection. Our results show that CCR2 deficiency reduces pulmonary infiltration of Ly6C^hi and Ly6C^low monocytes and shifts macrophage differentiation away from an M1-like toward an M2-like phenotype. Mechanistically, CCR2 deficiency compromises macrophage endocytosis and survival, elevates ROS production, and activates the NLRP3 inflammasome, leading to Caspase-3/GSDME-mediated pyroptosis with increased IL-1β and IL-18, while suppressing the Caspase-1/GSDMD pathway. These findings were recapitulated in vitro using C. muridarum-stimulated Ccr2-deficient bone marrow-derived macrophages (BMDMs), which also showed impaired migration, reduced M1-like polarization, diminished endocytosis, and enhanced ROS/NLRP3/pyroptosis. Furthermore, co-culture of these BMDMs with CD4⁺ T cells revealed that Th1 differentiation was inhibited, whereas Th2 and Th17 responses were promoted. Collectively, CCR2 orchestrates monocyte–macrophage function by driving M1-like polarization and inhibiting NLRP3/Caspase-3/GSDME pyroptosis to rebalance Th1/Th2/Th17 immunity, thereby enhancing bacterial clearance while mitigating immunopathological tissue damage during Chlamydia infection. Full article

Immune checkpoint inhibitors targeting the PD-1 (Programmed Cell Death Protein 1)/PD-L1 (Programmed Death-Ligand 1) axis have transformed cancer therapeutics, yet their efficacy in gynecologic malignancies particularly high-grade serous ovarian carcinoma remains disappointingly limited. This therapeutic resistance stems from a highly orchestrated, multidimensional immunosuppressive tumor microenvironment (TME) characterized by the convergent actions of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and an inhibitory cytokine network (IL-10, TGF-β, VEGF). Emerging evidence positions TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) as a master checkpoint integrator that coordinately regulates CD8+ T-cell exhaustion, NK-cell dysfunction, and Treg-mediated suppression. Dual blockade of PD-1 and TIGIT represents a mechanistically rational strategy to dismantle this immunosuppressive fortress. This review synthesizes current understanding of the gynecologic TME architecture, delineates the molecular and cellular basis for TIGIT/PD-1 synergy, critically evaluates ongoing clinical translation efforts, and proposes an integrative framework leveraging spatial transcriptomics, single-cell resolution immunoprofiling, and patient-derived experimental models to accelerate biomarker-driven therapeutic development. Full article

Background/Objectives: Although influenza A viruses with partially truncated NS1 proteins are substantially attenuated and immunogenic due to enhanced innate immune activation; residual NS1-mediated antagonism of antiviral innate responses may support viral replication in the lower respiratory tract and constrain optimal immune responses. Strategies to further improve their immunogenicity and protective efficacy by incorporating immunomodulatory cytokines, such as IL-2, have been successfully explored. Methods: Here, we extended this approach to chemokine expression by engineering an NS1-truncated PR8-based virus (PR8/NS124) to express the immunomodulatory chemokine CXCL10 from the NS segment and compared it with the parental vector. Results: The recombinant NS124_SS_CXCL10 virus replicated to high titers in embryonated chicken eggs and MDCK cells. In vivo, however, CXCL10 expression reduced viral replication in mouse lungs by ~10⁴-fold, resulting in a near-non-replicating phenotype. In contrast to the parental virus, the vector did not induce weight loss and exhibited a strongly attenuated phenotype. This effect was associated with altered innate immune signaling, including increased IRF7 expression and early induction of IFN-α responses in the lungs, together with modulation of TLR-dependent sensing pathways in the upper respiratory tract. Despite severely impaired replication, intranasal immunization induced antigen-specific T-cell responses comparable to those elicited by the parental vector. Following intraperitoneal immunization, when replication of both vectors was minimal, the CXCL10-expressing vector induced significantly higher frequencies of antigen-specific CD8⁺ and CD4⁺ effector-memory T cells. This was accompanied by enhanced antigen-specific T-cell recall responses in the lungs following intranasal challenge. Importantly, the CXCL10-expressing vector demonstrated protective efficacy comparable to that of the parental NS124 vector against heterologous H3N2 challenge while exhibiting an improved safety profile. Conclusions: These findings support the incorporation of CXCL10 as a strategy to improve the safety and T-cell immunogenicity of NS1-truncated influenza vectors. Full article