Cascade-activatable nanotheranostics for near-infrared fluorescence imaging-guided photoimmunotherapy.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy by enhancing antitumor immunity but are associated with immune-related adverse events, including myocarditis. Although T cell involvement in ICI-associated myocarditis is well established, the contribution of myeloid-specific programmed death-ligand 1 (PD-L1) signaling to cardiac immune regulation remains unclear. To investigate the role of myeloid-specific PD-L1 in maintaining cardiac immune homeostasis, we generated a myeloid-specific PD-L1 conditional knockout (KO) mouse model using LysMCre-driven deletion. Cardiac function was assessed by echocardiography. Immune profiling of cardiac and systemic compartments was performed using flow cytometry, quantitative PCR, ELISA, and histological analyses. In vitro coculture assays were conducted to assess macrophage-fibroblast (FB) and macrophage-T cell interactions. Myeloid PD-L1 KO mice exhibited early-onset cardiac dysfunction, reduced left ventricular ejection fraction, left ventricular fractional shortening, and upregulated heart failure markers. Immune profiling revealed systemic and myocardial inflammation, with increased C-C chemokine receptor type 2 macrophages and activated T cells. Coculture assays confirmed that PD-L1-deficient myeloid cells enhance T cell activation, Th17 polarization, and FB-mediated fibrotic gene expression. Myeloid-specific PD-L1 plays a critical role in limiting inflammation and maintaining cardiac integrity. Its deficiency promotes a proinflammatory microenvironment, contributing to cardiac dysfunction and implicating it as a key player in ICI-associated myocarditis. These findings identify myeloid PD-L1 as a potential therapeutic target to mitigate immune-mediated cardiotoxicity.NEW & NOTEWORTHY Immune checkpoint inhibitor-associated myocarditis is incompletely understood beyond T cell-driven mechanisms. This study identifies myeloid-specific PD-L1 as a critical regulator of cardiac immune homeostasis. Loss of myeloid PD-L1 triggers early myocardial inflammation, immune cell infiltration, FB activation, and subsequent cardiac dysfunction. These findings uncover a previously unrecognized myeloid checkpoint pathway contributing to immune-mediated cardiotoxicity and highlight myeloid PD-L1 as a potential therapeutic target.

Targeting mir130b-IL-33-PD-L1 axis effectively inhibits esophageal squamous carcinoma progression.

Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule that negatively regulates T-cell activation and serves as a characteristic marker of exhausted T cells in bacterial and viral infections. In this study, we found that Enterococcus faecalis (E. faecalis) infection modulated macrophage immune function under inflammatory conditions by upregulating PD-L1 expression. The aim of this study was to investigate the effect and potential regulatory mechanisms of E. faecalis and its virulence factor lipoteichoic acid (LTA) on the expression of PD-L1 in macrophages. RAW264.7 cells were treated with E. faecalis or LTA, respectively. Cellular immunofluorescence staining, flow cytometry, quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were employed to assess the expression of PD-L1 and endoplasmic reticulum (ER) stress-related proteins, including inositol-requiring enzyme 1 α (IRE1 α) and X-box binding protein 1 (XBP1), in macrophages. Following inhibition of the IRE1 α/XBP1 pathway and treatment with E. faecalis, qRT-PCR, flow cytometry, and WB were performed to detect the expression of PD-L1 and XBP1. Macrophage apoptosis was quantified by flow cytometry. Toll-like receptor 2 (TLR2) was knocked down using small interfering RNA (siRNA), and the expression of PD-L1, IRE1 α, and XBP1 in TLR2-silenced macrophages stimulated by E. faecalis was evaluated by qRT-PCR and WB. Statistical significance was analyzed using the Mann-Whitney test and Kruskal-Wallis test. The results demonstrated that E. faecalis and LTA significantly enhanced the expression of PD-L1, IRE1 α, and XBP1s in macrophages. Inhibition of the IRE1 α/XBP1 pathway reduced XBP1s and PD-L1 expression as well as apoptosis in E. faecalis-stimulated macrophages. TLR2 silencing decreased PD-L1, IRE1 α, and XBP1s expression levels in E. faecalis-stimulated macrophages. These findings reveal a novel mechanism by which E. faecalis induces persistent apical periodontitis and provide a foundation for further exploration of immune checkpoint molecules in the pathogenesis and treatment of this disease.

Targeting PD-L1 and disrupting Siglec-9 cooperatively potentiate macrophage phagocytosis of breast cancer via a trispecific macrophage engager (TriME).

A novel microtubule inhibitor modulates the myeloid PD-L1 expression, restores T cell effector function, and promotes apoptosis for effective suppression of colorectal cancer.

Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting STAT1 or STAT3 did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia.NEW & NOTEWORTHY Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.

Background: Ankylosing spondylitis (AS) represents a chronic inflammatory arthropathy characterized by aberrant immune regulation. Immune checkpoint molecules, including Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4), Programmed Death-1 (PD-1), and Programmed Death-Ligand 1 (PD-L1), serve as critical modulators of immune homeostasis. Their dysregulation may contribute to the pathogenesis of autoimmune disorders. Objectives: evaluate the diagnostic and prognostic potential of soluble immune checkpoint molecules (sPD-1, sPD-L1, and sCTLA-4) as biomarkers for disease activity and progression in patients with ankylosing spondylitis. Methodology: This case-control study enrolled 50 patients with confirmed AS and 50 age- and sex-matched healthy controls. Serum levels of sPD-1, sPD-L1, and sCTLA-4 were quantified using enzyme-linked immunosorbent assay (ELISA). Disease activity was assessed using standardized clinical indices. Statistical analyses included parametric and non-parametric tests, correlation analyses, and multivariate regression models. Result: Patients with AS demonstrated significantly elevated sCTLA-4 levels (2.82±0.41 ng/mL) compared to controls (2.12±0.28 ng/mL, p<0.001). Conversely, sPD-1 (5.43 ± 0.52 ng/mL vs. 6.31 ± 0.47 ng/mL, p<0.001) and sPD-L1 (5.01 ± 0.63 ng/mL vs. 6.24 ± 0.58 ng/mL, p<0.001) were significantly reduced in AS patients. Early-stage disease (<5 years) showed distinct checkpoint profiles compared to late-stage disease (≥5 years), with sCTLA-4 levels correlating positively with disease duration (r=0.68, p<0.001). Levels of soluble immune checkpoint molecules are altered in AS: there are increased levels of sCTLA-4 coupled with decreased levels of sPD-1/sPD-L1. Conclusion: These novel biomarkers could eventually be used for disease monitoring and prognosis; they therefore need further investigation in longitudinal cohorts.

Checkpoint inhibitors, a class of immunotherapeutic agents, have transformed the oncology landscape by targeting immune checkpoints - regulatory pathways that modulate immune cell activity. By inhibiting proteins such as programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), these agents enhance the immune response against cancer cells. However, their efficacy comes at the cost of a range of immune-related adverse events (irAEs), including autoimmune reactions such as colitis, hepatitis, and endocrinopathies, which can range in severity from mild to life-threatening. We present the case of a 76-year-old man with cholangiocarcinoma on durvalumab, a PD-L1 inhibitor, who presented to the emergency department with shortness of breath, cough, and weakness. Workup led to the diagnosis of immune-related myasthenia gravis and a non-ST-elevation myocardial infarction (NSTEMI), the latter believed to be secondary to durvalumab-induced myocarditis. Initial treatment with intravenous immunoglobulin (IVIG) produced brief, partial symptomatic improvement but failed to resolve respiratory weakness or other bulbar manifestations. His condition deteriorated rapidly, progressing to respiratory failure within weeks of onset. Given the refractory nature of his disease course, he was subsequently treated with a repeat dose of IVIG and prednisone, then transferred to an outside facility for plasma exchange. Despite these interventions, the patient ultimately succumbed to his illness. This case highlights the rare but potentially fatal concurrent occurrence of immune-related myasthenia gravis and myocarditis as irAEs in a patient receiving durvalumab for cholangiocarcinoma. While checkpoint inhibitors have revolutionized outcomes across many solid tumor malignancies, this case underscores the diagnostic and management challenges posed by severe, refractory irAEs, and the importance of early recognition and aggressive treatment in this patient population.

Engineered biohybrids for photothermally enhanced chemodynamic-immunotherapy through reprograming immunosuppressive microenvironment and inhibiting immune evasion.

Regulatory B cells (Bregs) are a functionally defined yet phenotypically heterogeneous subset of lymphocytes that are essential for maintaining immune homeostasis. Their canonical function is regulated through the secretion of interleukin-10 (IL-10), a potent anti-inflammatory cytokine. However, accumulating evidence indicates that other molecules, such as IL-35 and transforming growth factor-β, and that of contact-dependent pathways, such as Programmed Cell Death Ligand-1(PD-L1) and Programmed Cell Death-1(PD-1), also play indispensable roles in their regulatory arsenal. This review examines the immunoregulatory roles of Bregs across diverse clinical contexts, including infectious diseases, cancers, autoimmune disorders (such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and uveitis), and organ transplantation. Crucially, we highlight a fundamental functional dichotomy: although Bregs confer protection against autoimmunity and promote transplant tolerance, they concurrently drive the progression of chronic infections and malignancies by dampening antipathogen and antitumor immune responses. This functional dichotomy highlights the complexity of immune regulation, where Bregs act as critical nodes balancing health and pathology. The immense therapeutic potential by modulating Bregs activity and unresolved questions that will guide the future frontiers of Bregs research are essentially discussed.

Programmed death ligand 1 (PD-L1) expression, assessed by the combined positive score (CPS), is an established predictive biomarker for first-line chemo-immunotherapy in metastatic triple-negative breast cancer (mTNBC). In routine practice, CPS testing is heterogeneous and its relationship with outcomes in later-line, sacituzumab govitecan (SG)-treated patients with mTNBC is not well described. We aimed to assess clinicopathological correlates of CPS and its association with survival in this cohort. We conducted a retrospective, multicenter study within the Central European Breast Cancer Collaboration (CEBCC)-102 project. CPS was locally assessed by validated immunohistochemistry. Survival outcomes: overall survival (OS), post-metastatic survival (PMS), and metastasis-free interval, were assessed with the Kaplan-Meier method. Of 303 women from the Czech Republic, Poland, and Slovakia with mTNBC treated with SG in ≥ 2 line, 107 (35.3%) with available CPS results were included in this analysis. CPS was positive (≥ 10) in 51/107 patients (47.7%) without significant demographic or disease-specific differences. During a median follow-up of 40months, CPS-positive status may suggest worse outcomes in this cohort in multivariate analysis despite partial first-line chemo-immunotherapy exposure: OS 41.6 versus 67.7months (HR 2.2, 95% CI: 1.1-4.5, p = 0.027) and PMS 20.2 versus 27.1months (HR = 2.3, 95% CI: 1.2-4.2, p = 0.009). In this selected cohort, CPS status did not correlate with clinicopathological characteristics, but CPS-positive status was associated with inferior survival outcomes. Given the selection and survivor bias inherent to later-line treatment cohorts and the incomplete availability of CPS, these findings should be considered hypothesis-generating.

IO102-IO103 immune-modulatory cancer vaccine and pembrolizumab in melanoma.

In the global phase 3 RATIONALE-306 study (NCT03783442), first-line tislelizumab plus chemotherapy showed significant overall survival (OS) benefit versus chemotherapy alone for unresectable locally advanced/metastatic esophageal squamous cell carcinoma (ESCC). We report post hoc results for the Japanese subgroup. Eligible Japanese patients were randomized (1:1) to tislelizumab 200mg or placebo every 3weeks plus chemotherapy (cisplatin plus fluoropyrimidine) and included in the Japanese analysis set. Endpoints included OS, progression-free survival (PFS), objective response rate (ORR), OS in patients with programmed death-ligand 1 (PD-L1) Tumor Area Positivity (TAP) score ≥ 10%, and safety. Overall, 66/649 (10.2%) patients were randomized in Japan (n = 33 per arm). After a minimum follow-up of 37.9months (data cutoff November 24, 2023), tislelizumab plus chemotherapy showed improvements in median OS versus placebo plus chemotherapy (24.5 vs. 15.1months; hazard ratio [HR]: 0.75; 95% CI 0.43-1.30). An improvement in OS was also seen in patients with PD-L1 TAP score ≥ 10% (HR: 0.79; 95% CI 0.26-2.36). There was improvement in median PFS (HR: 0.77; 95% CI 0.45-1.32) and a higher ORR (63.6% vs. 45.5%) in the tislelizumab plus chemotherapy versus placebo plus chemotherapy arm, respectively. Treatment-related adverse events (TRAEs) with tislelizumab plus chemotherapy versus placebo plus chemotherapy occurred in, respectively, 45.5% versus 36.4% (any-grade) and 27.3% versus 6.1% (grade ≥ 3) of patients. No TRAE-related deaths occurred. After 3years, first-line tislelizumab plus chemotherapy demonstrated sustained efficacy and a tolerable safety profile in Japanese patients with unresectable locally advanced/metastatic ESCC, consistent with the global RATIONALE-306 population.

Patients with high-risk muscle-invasive bladder cancer (MIBC) remain at substantial risk of disease recurrence. Randomized phase 3 trials have evaluated adjuvant programmed cell death 1 (PD-1) inhibitors in this setting, but the magnitude and consistency of benefit across patient subgroups remain incompletely defined. We performed a systematic review and meta-analysis of randomized phase 3 trials comparing adjuvant PD-1 inhibitors with placebo or observation in patients with resected high-risk MIBC. HRs for disease-free survival (DFS) and overall survival (OS), as well as risk ratios for adverse events, were pooled using random-effects models. Prespecified subgroup analyses were conducted according to PD-L1 (programmed death-ligand 1) expression and prior receipt of cisplatin-based neoadjuvant chemotherapy. Two phase 3 trials encompassing patients treated with adjuvant nivolumab or pembrolizumab were included. Adjuvant PD-1 inhibitor therapy significantly improved DFS compared with control (pooled HR <1), with consistent benefit observed across PD-L1-defined subgroups and regardless of prior neoadjuvant cisplatin use. A favorable trend toward improved OS was observed, although survival data remain immature. Treatment was associated with a higher incidence of grade 3 or higher and immune-related adverse events compared with placebo or observation. Among patients with resected high-risk MIBC, adjuvant PD-1 inhibitor therapy significantly improves DFS with an acceptable safety profile. However, owing to the limited number of studies and short follow-up periods, these findings should be considered preliminary, and longer follow-up is required to confirm any potential OS benefit.

A resveratrol derivative RVX-208 inhibits PD-1/PD-L1 to restrain non-small cell lung cancer as an immunotherapy.

Pulmonary microbiota is a hidden link between lung cancer Development and microenvironment: Potential for future immune therapeutic strategies.

Genetically engineered cellular membrane-camouflaged nanoparticles amplify immune response against recurrent metastatic triple-negative breast cancer.

To evaluate the correlation between time-dependent diffusion MRI (td-dMRI) parameters and prognostic factors in nasopharyngeal carcinoma (NPC). 116 patients (105 NPC, 11 benign hyperplasia) were prospectively enrolled. Four td-dMRI-derived microstructural parameters, extracellular diffusivity (Dex), intracellular volume fraction (Vin), Diameter, and Cellularity, and apparent diffusion coefficient (ADC) at three oscillation frequencies (ADC0Hz, ADC30Hz, and ADC55Hz), were obtained. TNM stages and prognostic factors were recorded; continuous variables were dichotomized by optimal cut-offs. Correlations, between-group comparisons, and receiver operating characteristic analysis summarized diagnostic performance as the area under the curve (AUC). Programmed death ligand 1 was correlated with ADC values, with ADC55Hz achieving an AUC of 0.708. Epidermal growth factor receptor was correlated with Cellularity and Diameter (r = 0.341 and -0.329). Ki-67 expression was associated with Dex and ADC55Hz (r = 0.252 and 0.286). Vin, Cellularity and ADC0/30Hz were linked to histological subtype, with Vin achieving the highest AUC of 0.706. TNM stages were correlated with Diameter (r = 0.203 to 0.371) and Cellularity (r = -0.365 to -0.284). ADC30Hz best distinguished NPC (T1-2) from hyperplasia (AUC = 0.847). Negative correlations were observed between several parameters and Epstein-Barr virus (EBV)-based antibodies (r = -0.269 to -0.239). Vin and ADC0/30Hz differed across EBV DNA clearance groups after induction chemoimmunotherapy (p ≤ 0.038). td-dMRI-measured diameters correlated with pathological measurements (r = 0.772, p < 0.001). td-dMRI parameters may reflect tumor microstructure and show associations with prognostic factors in NPC, suggesting potential utility for risk stratification and treatment monitoring. Question Can microstructural parameters from time-dependent diffusion MRI (td-dMRI) noninvasively provide clinically meaningful prognostic information for nasopharyngeal carcinoma? Findings Differences in prognostic factor levels can be reflected by td-dMRI, and td-dMRI-derived diameter was correlated with pathology-derived diameter (r = 0.772, p < 0.001). Clinical relevance td-dMRI provides a noninvasive method to characterize tumor microstructure, potentially improving patient management strategies in nasopharyngeal carcinoma.

Recruitment of tumor-associated macrophages via the CCL4-CCR5 axis promotes immune escape through PD-1 signaling in lung adenocarcinoma.