Immunotherapeutics against triple-negative breast cancer (TNBC) hold great promise. In this work, we provide a combination therapy for simultaneous increasing tumor immunogenicity and down-regulating programmed cell death ligand 1 (PD-L1) to boost antitumor immunity in TNBC. We prepare bis (diethyldithiocarbamate)-copper/indocyanine green nanoparticles (CuET/ICG NPs) simply in aqueous with one-pot method. CuET/ICG NPs interfere mitochondria, reduce oxygen consumption, and alleviate tumor hypoxia to potentiate photodynamic therapy (PDT) for amplifying immunogenic cell death (ICD). Meanwhile, mitochondria dysfunction leads to energy stress and activates AMPK pathway. As a result, CuET/ICG NPs downregulates membrane PD-L1 (mPD-L1) on both 4T1 cancer cells and cancer stem cells (CSCs) through AMP-activated protein kinase (AMPK)-mediated pathway in hypoxia. Cooperatively, the combinational therapy activates antitumor immunity and triggers long lasting immune memory response to resist tumor re-challenge. Our study represents an attempt that conquers tumor immunosuppressive microenvironment with simple biomedical materials and multimodality treatments.

Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.

Chronic obstructive pulmonary disease (COPD) and lung cancer are associated diseases. COPD confers a negative prognosis in NSCLC, but the clinical benefit of immune checkpoint inhibitors (ICI) in this population is unclear. A population-level analysis of patients in Ontario, Canada was performed through the ICES (formerly known as the Institute for Clinical Evaluative Sciences) administrative database. Patients with NSCLC and treated with PD-1/PD-L1 immune checkpoint inhibitors between Jan 2010 and Dec 2020 were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using Cox proportional hazards regression. Hospitalizations and duration of treatment were compared secondarily using logistic and linear regression. A total of 4306 patients received ICI and 54% of patients had a diagnosis of COPD. Median (95% CI) OS was 9.2 (8.5-9.9) months for patients with COPD and 8.2 (7.3-8.8) for patients without COPD, which was not significantly different (adjusted hazard ratio (aHR) = 0.94, 95% CI, 0.87-1.01, P = 0.092). Similarly, the median time on treatment was not different (85 vs. 99 days, multivariable P = 0.10). However, the 90-day hospitalization rate was decreased in the COPD population (multivariable odds ratio 0.76, 95% CI 0.62-0.94, P = 0.011). Among patients with NSCLC receiving ICI, our data suggest that a diagnosis of COPD does not result in shortened treatment, poorer survival, or higher rates of hospitalization. COPD itself should not be considered a contraindication to ICI.

The cellular uptake and tissue dispersion efficiency of nanomedicines are crucial for realizing their biological functionality. As a cutting-edge category of nanomedicine, covalent organic frameworks (COFs)-based photosensitizers, have been extensively employed in cancer phototherapy in recent years. However, the inherent aggregation tendency of COFs hinders their uptake by tumor cells and dispersion within tumor tissues, thereby limiting their therapeutic efficacy. In this study, we employed Fusobacterium nucleatum (F.n.), a prevalent intratumoral bacterium, to construct a bacterium membrane-wrapped COF, COF-306@FM, which is readily taken up by cancer cells and uniformly dispersed within tumor tissues. Meanwhile, the F.n. membrane can also serve as an immune adjuvant to warm up the "cold" tumor immune microenvironment by enhancing the CD8+ T and B cells infiltration, and inducing the formation of tumor-located tertiary lymphoid structures. Consequently, the response rate of αPD-L1 immunotherapy was drastically promoted to efficiently prevent tumor metastasis and recurrence, causing 84.6 % distant tumor inhibition and complete suppression of tumor metastasis. In summary, this innovative approach not only enhances the therapeutic potential of COFs but also opens up new avenues for integrating microbial and nanotechnological strategies in cancer treatment.

Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.

Mutual exclusion of gene expression has received limited attention. Gene (expression) plasticity analysis provides an efficient way to identify highly plastic genes (HPGs) based on changes in expression rank. In this study, we quantitatively measured the expression plasticity of 19 961 protein-coding genes in 24 human cancer cell lines and identified HPGs in these cells. By comparing methods, we showed that virtual sorting and cosine similarity, rather than Pearson and Spearman rank correlations, are suitable for mutual exclusion. Mutually exclusive gene pairs were identified in each cell type. Experimental validation showed that thiol methyltransferase 1B (TMT1B; also known as METTL7B) and CD274 molecule (CD274; also known as PD-L1) were mutually exclusively expressed at either the mRNA or protein level. METTL7B negatively regulated PD-L1 expression in several cell types, and the JAK/STAT3 pathway was involved. Knockdown of METTL7B in Huh7 cells inhibited interleukin 2 (IL-2) secretion by Jurkat cells in co-culture experiments, and the inhibition was blocked by anti-PD-L1 antibodies. Therefore, this study provides an efficient method of expressional mutual exclusion and implies a newly identified intergenic regulatory paradigm.

The VRK2 ser-thr kinase, belonging to the dark kinome, is implicated in the pathogenesis of cancer progression, neurological and psychiatric diseases. The VRK2 gene codes for two isoforms. The main isoform (VRK2A) is mainly located in the cytoplasm, and anchored to different types of membranes, such as the endoplasmic reticulum, mitochondria and nuclear envelope. The VRK2A isoform interacts with signaling modules assembled on scaffold proteins such as JIP1 or KSR1, forming stable complexes and blocking the activation of regulatory signaling pathways by altering their intracellular localization and the balance among them. VRK2 regulates apoptosis, nuclear membrane organization, immune responses, and Cajal bodies. Wild-type VRK2 is overexpressed in tumors and contributes to cancer development. In cells and tumors with low levels of nuclear VRK1, VRK2 generates by alternative splicing a shorter isoform (VRK2B) that lacks the C-terminal hydrophobic tail and permits its relocation to nuclei. Furthermore, rare VRK2 gene variants are associated with different neurological or psychiatric diseases such as schizophrenia, epilepsy, bipolar disorder, depression, autism, circadian clock alterations and insomnia, but their pathogenic mechanism is unknown. These diseases are a likely consequence of an altered balance among different signaling pathways that are regulated by VRK2.

This study aimed to elucidate the underlying mechanisms regarding microRNA-708-5p (miR-708-5p) in lung adenocarcinoma (LUAD). Here, the co-culture system of LUAD cells and macrophages, as well as a xenograft mouse model, were established. High levels of miR-708-5p were observed in LUAD. Exosomal miR-708-5p facilitated M2-like phenotype polarization, whereas miR-708-5p inhibition blocked the polarization. Exosomal miR-708-5p was identified as a pivotal signaling molecule for macrophages to mediate tumor cell proliferation, invasion, migration and IFN-γ production in T cells. In addition, miR708-5p was observed to induce PD-L1 expression, and PD-L1 silencing inhibited macrophage-induced tumor cell growth behavior and regulated CD8 T cell activity. In xenograft models, miR-708-5p inhibition and PD-L1 silencing attenuated macrophage-induced tumor growth, induced IFN-γ secretion and CD8 expression, and modulated the PTEN/AKT/mTOR pathway. In LUAD patients, there was an upregulation of both miR-708-5p and PD-L1 expression, accompanied by the activation of PTEN/AKT/mTOR. In conclusion, this study demonstrated the induction of M2 macrophage polarization and PD-L1 expression by exosomal miR-708-5p. We observed that exosomal miR-708-5p mediated the PTEN/AKT/mTOR pathway, diminished CD8 T cell activity and accelerated LUAD progression. The inhibition of specific exosomal miRNA secretion and anti-PD-L1 in the LUAD microenvironment may represent a promising avenue for LUAD immunotherapy.

The development of resistance significantly hampers the efficacy of immunotherapies in cancer treatment. The combination of JQ1, a BRD4 protein inhibitor, and anti-programmed death ligand 1 (PD-L1) immunotherapies has a synergic therapeutic potential to treat solid tumors. This study aimed to evaluate the potential of immuno-PET imaging for measuring pharmacodynamic biomarkers in response to this combination therapy targeting PD-L1. Methods: We synthesized different radioligands derived from the anti-PD-L1 C4 antibody and a minibody targeting murine CD8α for immuno-PET imaging. We conducted experiments on human non-small cell lung cancer and mouse colorectal carcinoma animal models to assess the efficacy of JQ1 and avelumab treatment on PD-L1 expression and immune cell infiltration by immuno-PET imaging. Taking advantage of the unique properties of the C4-derived minibody, we measured PD-L1 occupancy in tumors after treatment. Results: JQ1 efficiently reduced PD-L1 extracellular expression across all tested cell lines in vitro and in vivo. Avelumab and JQ1 treatments alone or in combination led to significant tumor growth reduction in the immunocompetent murine colorectal carcinoma model, reducing mean tumor growth from 725% in the control group to 125% in the combination group. Treatments also significantly increased the survival of mice by 4-12 d compared with the control group. Although imaging CD8-positive T-cell infiltration did not predict tumoral response, imaging the unoccupied fraction of PD-L1 after treatment was predictive of tumor growth reduction and survival. Conclusion: Immuno-PET imaging with noncompetitive radioligands throughout the treatment course could improve the efficiency and support rationalization of the dosing regimen of immunotherapies.

Toll-like receptors (TLRs) are central components of the innate immune system as they recognize molecular patterns associated with pathogens and cellular damage and initiate immune responses using MyD88- and TRIF-dependent pathways. In contrast to being very useful for immune defense, dysregulated TLR signaling may be involved in diseases, such as cancer and autoimmune conditions. In cancer, TLRs create an environment that supports tumorigenesis and growth. In addition to this, a class of multifunctional noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, regulate gene expression without encoding proteins. MiRNAs regulate gene expression in a fine-tuned manner, while lncRNAs and circRNAs do so via diverse mechanisms. Notably, these ncRNAs interact, where lncRNAs and circRNAs function as competing endogenous RNAs and ceRNA, affecting miRNA activity. This interaction has a vital role in cancer pathology, in influencing that of various oncogenes and tumor suppressors in the tumor microenvironment; hence, modulation of ncRNAs could also be a great promising therapeutic approach. In this context, interplay between TLRs and ncRNAs is of paramount importance as they influence various parameters of the tumor microenvironment. TLR signaling works upon the expression of ncRNAs, while ncRNAs work back to regulate TLR signaling in return. An example of this includes miRNA targeting of components of the TLR; lncRNAs induced by TLR signaling possibly would favor tumor progression. Pharmacological interventions directed toward inhibiting these TLR pathways could be the model to halt malignancy by hampering pro-tumor inflammation and boosting immune responses against neoplasms. Hence, the review will highlight the complicated contrast of ncRNAs and TLRs within human cancer. By connecting the mechanisms, the researchers may study more about tumorigenesis and gather up new, innovative notions regarding therapeutic targeting.

Programmed cell death protein 1 (PD-1) and its primary ligand PD-L1 are integral components of a significant immune checkpoint pathway, widely recognized for its central role in cancer immunotherapy. However, emerging evidence highlights their broader involvement in both the central and peripheral nervous systems. In this study, we demonstrate that PD-L1/PD-1 signaling in astrocytes during mouse brain development regulates astrocyte maturation and morphogenesis via the MEK/ERK pathway by targeting the downstream effector cysteine and glycine rich protein 1 (CSRP1). This enhanced astrocyte morphological complexity results in increased end-foot coverage of blood vessels. Additionally, aberrant secretion of CSRP1 by astrocytes interacts with oligodendrocyte precursor cells (OPCs) membrane proteins annexin A1 (ANXA1) and annexin A2 (ANXA2), leading to the exclusion of migrating OPCs from blood vessels. This disruption in OPC migration and differentiation results in abnormal myelination and is associated with cognitive deficits in the mice. Our results provide critical insights into the function of PD-L1/PD-1 signaling in astrocyte-OPC interactions and underscore its relevance to glial cell development and pathogenesis in neurodevelopmental disorders.

The treatment of gastric cancer remains challenging, with immunotherapy serving as a critical component of the holistic approach to its treatment. The results of this study indicated that statins could decrease the serum levels of interleukin-enhancing binding factor 3 (ILF3) and programmed cell death ligand 1(PD-L1) in GC patients and improve their prognosis. Functional experiments demonstrated that simvastatin induced ferroptosis by inhibiting ILF3 in GC cells and enhanced the killing effect of activated CD8+ T cells on GC cells. The CUT&Tag assay revealed that, mechanistically, simvastatin inhibited ILF3 expression by reducing the acetylation level at residue site H3K14 in ILF3. Next-generation sequencing and Kyoto Encyclopedia of Genes and Genomes analysis revealed that ILF3 regulated PD-L1 expression through the DEPTOR/mTOR signaling pathway. Overall, simvastatin induced ferroptosis in GC cells by inhibiting ILF3 expression while promoting the activation of CD8+ T cells to augment antitumor immune responses, thereby facilitating synergistic immunotherapy.

The immunotherapy targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death ligand-1 (PD-L1) has achieved significant breakthroughs, but further improvements are still needed in cancer treatment.

We investigated orlistat, a drug approved by the Food and Drug Administration for the treatment of obesity and found that it can enhance the efficacy of CTLA-4 blockade immunotherapy. We conducted both in vivo and in vitro experiments to explore the mechanism by which orlistat increased antitumor immunity.

Orlistat enhances the efficacy of anti-CTLA-4 immunotherapy by suppressing tumor cell PD-L1 protein expression and boosting the transcription of interferon-stimulated genes (ISGs) and MHC-I. Mechanistically, orlistat inhibits AKT activity and subsequent phosphorylation of forkhead box O3a (FOXO3a) at its threonine (T) 32, serine (S) 253, thereby downregulating Forkhead box M1 (FOXM1) expression, which ultimately suppresses PD-L1 transcription. Specifically, inhibition of FOXM1 leads to FOXO3a accumulation through impaired AKT activity. FOXM1 activates protein kinase B (AKT) via acting as a scaffold to facilitate 3-phosphoinositide-dependent protein kinase 1 (PDK1) and AKT and interaction. In addition, orlistat enhances phosphorylated signal transducer and activator of transcription 1 (p-STAT1) at tyrosine (Y) 701, resulting in upregulation of ISGs and MHC-I.

Orlistat plays a crucial role in modulating the immune response and supporting the combination with CTLA-4 blockade to promote antitumor immunotherapy.

Ferroptosis represents a distinctive and distinct form of regulated cellular death, which is driven by the accumulation of lipid peroxidation. It is distinguished by altered redox lipid metabolism and is linked to a spectrum of cellular activities, including cancer. In breast cancer (BC), with triple negative breast cancer (TNBC) being an iron-and lipid-rich tumor, inducing ferroptosis was thought to be a novel approach to killing breast tumor cells. However, in the recent past, a novel conceptual framework has emerged which posits that in addition to the promotion of tumor cell death, ferritin deposition has a potent immunosuppressive effect on the tumor immune microenvironment (TIME) via the influence on both innate and adaptive immune responses. TIME of BC includes various cell populations from both the innate and adaptive immune systems. In this review, the internal association between iron homeostasis and the progression of ferroptosis, along with the common inducers and protectors of ferroptosis in BC, are discussed in detail. Furthermore, a comprehensive analysis is conducted on the dual role of ferroptosis in immune cells and proto-oncogenic functions, along with an evaluation of the potential applications of immunogenic cell death-targeted immunotherapy in TIME of BC. It is anticipated that our review will inform future research endeavors that seek to integrate ferroptosis and immunotherapy in the management of BC.

Recent years, immunotherapy has emerged as a pivotal approach in cancer treatment. However, the response of gastric cancer to immunotherapy exhibits significant heterogeneity. Therefore, the early identification of gastric cancer patients who are likely to benefit from immunotherapy and the discovery of novel therapeutic targets are of critical importance.

We collected data from European Nucleotide Archive (ENA) and Gene Expression Omnibus (GEO) databases. In project PRJEB25780, we performed WGCNA analysis and Lasso regression and chose CXCR2P1 for the subsequent analysis. Then, we compared the expression difference of CXCR2P1 among different groups. Kaplan-Meier curve was used to analyze the prognostic value of CXCR2P1, which was validated by project IMvigor210 and GEO datasets. ESTIMATE and CIBERSORT algorithm were used to evaluate the reshaping effect of CXCR2P1 to immune microenvironment of tumor. Differentially expressed genes (DEG) analysis, enrichGO analysis, Gene Set Enrichment Analysis (GSEA) and co-expression analysis were used to explore the cell biological function and signaling pathway involved in CXCR2P1.

WGCNA identified CXCR2P1 as a hub gene significantly associated with immune response to PD-1 inhibitors in gastric cancer. CXCR2P1 expression was elevated in responders and correlated with better prognosis. Functional analysis revealed its role in reshaping the tumor immune microenvironment by promoting immune cell infiltration, including M1 macrophages, activated CD4+ T cells, and follicular helper T cells. CXCR2P1 enhanced antigen presentation via the MHC-II complex, influenced key immune pathways, such as Toll-like receptor signaling and T-cell activation, which led to the up-regulation of expression of PD-L1. GSEA showed CXCR2P1 were correlated with microRNAs. Through DEG analysis and expression analysis, MIR215 was identified as a potential direct target of CXCR2P1.

High expression of CXCR2P1 is correlated with better response to PD-1 inhibitor. It reshapes the immune microenvironment by increasing immune infiltration and changing the fraction of immune cells. In tumor immune microenvironment, CXCR2P1 can promote inflammation, enhance antigen presentation and activate the PD-1/PD-L1-related signaling pathway, which might be achieved by CXCR2P1-MIR215 axis.

Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized clinical cancer treatment, while abnormal PD-L1 or HLA-I expression in patients can significantly impact the therapeutic efficacy. Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response. However, a systematic interpretation of cancer immune-related mutations is still lacking. Here, we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome, which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression. Beyond residues associated with phosphorylation events, our screens also identified functional mutations that affect mRNA or protein stability, DNA binding capacity, protein-protein interactions, and enzymatic catalytic activity, leading to either gene inactivation or activation. Notably, we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression, represented by the clinically relevant mutation SETD2_Y1666. We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models. Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance, offering valuable guidance for clinical diagnosis, ICB therapy, and the development of innovative drugs for cancer treatment.

New treatment strategies are urgently needed for patients with advanced cervical cancer (CC). Here, a synergistic anti-CC effect of a novel combinatorial immunotherapy with adoptively transferred autologous Vγ9Vδ2 T cells and αβ T cells is shown. The pivotal role of both circulating and tumor-infiltrating Vγ9Vδ2 T cells in anti-CC immunity is uncovered. Importantly, autologous Vγ9Vδ2 T cells show a synergistic anti-CC effect with αβ T cells not only through killing tumor directly, but also by promoting the activation and tumoricidal activity of syngeneic αβ T cells through antigen presentation, which can be further boosted by conventional chemotherapy. Moreover, Vγ9Vδ2 T cells can restore the tumoricidal function of αβ T cell through competitively binding to BTN3A1, a TCR-Vγ9Vδ2 ligand on CC cells upregulated by IFN-γ derived from activated αβ T cell. These findings uncover a critical synergistic effect of autologous Vγ9Vδ2 T cells and αβ T cells in immunotherapy of CC and reveal the underlying mechanisms.

Metabolic remodeling is the hallmark of cancer. In recent years, mitochondrial metabolism (MM) has been considered essential in tumorigenesis and cancer progression. Understanding the role of MM in cervical cancer (CC) can provide insights into disease progression and potential therapeutic targets.

Clinical data of CC patients was downloaded from the UCSC Xena dataset, and differentially expressed genes (DEGs) were identified between tumor and normal samples. MM-related genes (MMRGs) were screened from the MSigDB database. DEGs and MMRGs were then intersected to identify differentially expressed MMRGs. A prognostic risk model was constructed based on these intersecting genes through Cox regression analysis, and its association with the tumor microenvironment and immune checkpoint-related genes was evaluated. Hub genes' expression was evaluated in cells through qRT-PCR. Additionally, drug sensitivity analysis was conducted to explore potential therapeutic drugs.

We identified 259 overlapping genes between DEGs and MMRGs, with 55 being prognosis-related. Two molecular clusters were revealed, with C1 exhibiting poorer prognosis. A prognostic risk model comprising five genes (BDH1, MIR210, MSMO1, POLA1, and STARD3NL) was established, showing significant associations with survival outcomes of CC patients. Functional enrichment analysis revealed that DEGs between high- and low-risk groups were tightly associated with the immune system. Analysis of the immune microenvironment showed significant differences between different risk groups, with higher immune and ESTIMATE scores observed in the low-risk group. Additionally, expression levels of immune checkpoint-related genes were significantly correlated with the risk score. Drug sensitivity analysis identified potential therapeutic agents correlated with the expression of the five prognostic genes.

Our findings underscore the importance of MM in CC progression and provide potential therapeutic targets for CC.

In recent years, there has been a growing trend towards the utilization of immunotherapy techniques for the treatment of cancer. Some malignancies have acquired significant progress with the use of cancer vaccines, immune checkpoint inhibitors, and adoptive cells therapy. Scholars are exploring the aforementioned methods as potential treatments for advanced prostate cancer (PCa) due to the absence of effective adjuvant therapy to improve the prognosis of metastatic castration-resistant prostate cancer (mCRPC). Immunotherapy strategies have yet to achieve significant advancements in the treatment of PCa, largely attributed to the inhibitory tumor microenvironment and low mutation load characteristic of this malignancy. Hence, researchers endeavor to address these challenges by optimizing the design and efficacy of immunotherapy approaches, as well as integrating them with other therapeutic modalities. To date, studies have also shown potential clinical benefits. This comprehensive review analyzed the utilization of immunotherapy techniques in the treatment of PCa, assessing their advantages and obstacles, with the aim of providing healthcare professionals and scholars with a comprehensive understanding of the progress in this field.

Aberrant expression of programmed death ligand-1 (PD-L1) facilitates tumor immune evasion. Protein arginine methyltransferase 3 (PRMT3), a member of type I PRMT family, mediates asymmetric dimethylarginine (ADMA) modification of various substrate proteins. This study investigates the role of PRMT3 in PD-L1-associated tumor immunosuppression in hepatocellular carcinoma (HCC). Hepatocyte-specific knockout of Prmt3 significantly suppressed HCC progression in DEN-CCL4-treated mice. Knockout of Prmt3 in HCC cells markedly increased CD8+ T cell infiltration, and reduced lactate production in tumors. PRMT3 interacted with pyruvate dehydrogenase kinase 1 (PDHK1), asymmetric dimethylation of PDHK1 at arginine 363 and 368 residues and increased its kinase activity. The R363/368 K mutant or inhibition of PDHK1 by JX06 blocked the effect of PRMT3 on lactate production. JX06 treatment also attenuated the tumor-promoting role of PRMT3 in HCC in vitro and in vivo. Furthermore, RNA-seq analysis revealed that knockout of PRMT3 downregulates the tumor-associated immune checkpoint, PD-L1, in tumor tissues. Chromatin immunoprecipitation (ChIP) assay demonstrated that PRMT3 promotes lactate-induced PD-L1 expression by enhancing the direct binding of histone H3 lysine 18 lactylation (H3K18la) to the PD-L1 promoter. Tissue microarray analysis showed a positive correlation between PRMT3 and PD-L1 expression in HCC patients. Anti-PD-L1 treatment reversed PRMT3-induced tumor growth and restored CD8+ T cell infiltration. Our research links PRMT3-mediated metabolic reprogramming and immune evasion, revealing that the PRMT3-PDHK1-lactate-PD-L1 axis may be a potential target for improving the efficacy of immunotherapy in HCC.

An increasing number of clinical studies have highlighted the use of atezolizumab in tumor immunotherapy. However, There is still a lack of comprehensive research on its associated adverse events (AEs). To improve our understanding of its toxicological profile and to provide valuable clinical insights regarding into the effectiveness of immunotherapy, this study utilized data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to conduct a retrospective analysis of AEs linked to atezolizumab.

We extracted the reports of AEs related to atezolizumab from the FAERS database from the first quarter of 2004 to the first quarter of 2024. We quantified them using the reporting odds ratio (ROR) and proportional reporting ratio (PRR), along with chi-square value (χ²), and conducted systematic classification of the AE signal mining results through SAS 9.4 software.

A total of 19,563 valid reports were incorporated, involving 20 distinct system organ class categories. The AEs related to atezolizumab, reported at the preferred term level, mainly encompassed anemia [ROR 2.33, 95% confidence interval (CI) lower limit 2.09, PRR 2.31, χ² 255.977], febrile neutropenia (ROR 2.81, 95% CI lower limit 2.50, PRR 2.79, χ² 333.586), neutrophil count decreased (ROR 2.14, 95% CI lower limit 1.89, PRR 2.13, χ² 150.688), white blood cell count decreased (ROR 2.35, 95% CI lower limit 2.03, PRR 2.34, χ² 136.673), sepsis (ROR 2.21, 95% CI lower limit 1.91, PRR 2.20, χ² 117.741), alanine aminotransferase increased (ALT) (ROR 2.86, 95% CI lower limit 2.44, PRR 2.85, χ² 180.031), and aspartate aminotransferase increased (AST) (ROR 2.79, 95% CI lower limit 2.38, PRR 2.78, χ² 170.955).

Apart from various degrees of hepatotoxicity, such as increased ALT and AST, the immune-related hematological toxicity of atezolizumab should also be noted. In clinical practice, healthcare providers should always be vigilant for the occurrence of such medication-related AEs and take measures to enhance the safety of clinical medication use.

Non-small-cell lung cancer (NSCLC) represents a highly prevalent form of malignancy. 5-methylcytosine (m5C) methylation functions as a key post-transcriptional regulatory mechanism linked to cancer progression. The persistent expression of PD-L1 in tumor cells plays a pivotal role in facilitating immune evasion and promoting T-cell exhaustion. However, the involvement of m5C in NSCLC immune evasion remains inadequately understood. This study seeks to explore the function of the m5C methyltransferase NSUN2 in modulating PD-L1 expression and facilitating immune evasion in NSCLC. Our findings indicate elevated levels of NSUN2 and ALYREF in NSCLC, and both promote the growth of NSCLC cells and the progression of lung cancer. Moreover, the expression of PD-L1 in NSCLC tissues positively correlates with NSUN2 and ALYREF expression. We then discovered that PD-L1 acts as a downstream target of NSUN2-mediated m5C modification in NSCLC cells. Knocking down NSUN2 significantly reduces m5C modification of PD-L1 mRNA, thereby decreasing its stability via the m5C reader ALYREF-dependent manner. Furthermore, inhibiting NSUN2 enhanced CD8+ T-cell activation and infiltration mediated by PD-L1, thereby boosting antitumor immunity, as confirmed in both in vitro and in vivo experiments. Collectively, these results suggested that NSUN2/ALYREF/PD-L1 axis plays a critical role in promoting NSCLC progression and tumor cell immune suppression, highlighting its potential as a novel therapeutic strategy for NSCLC immunotherapy.

Background: Gastric cancer (GC) is the third leading cause of cancer-related death and is associated with high mortality and morbidity. Helicobacter pylori (HP) infection is the most important cause of GC. We aimed to identify the core genes of HP caused GC and further elucidate the underlying mechanisms. Methods: GC and HP associated gastritis (HPAG) gene expression data were sourced from Gene Expression Omnibus. Key genes affecting GC prognosis were identified using Cytoscape software. Patient groups were formed based on key gene expression, and the immune analyses were performed with R. MNU, derived from nitrite by HP, was given to GC mice (240ppm) for histology and fluorescence assays. For in vitro experiments, cells received MNU (20 μM) stimulation for 24 hours. Results: CD14 was the only key gene identified. A total of 412 GC patients were divided into CD14-high and CD14-low groups. The two groups showed significant differences in immune cell populations and immune checkpoints. In particular, there was a notable increase in M2 macrophages in GC patients with high CD14 expression (P <0.001). GC Patients with high CD14 expression exhibited a more pronounced immune response than those with low CD14 expression, and elevated CD14 expression positively correlated with the efficacy of CTLA4 therapy (P <0.05). These results indicated that CD14 expression was strongly correlated with the GC immune response. A noticeable increase in CD14 levels was observed in MNU-induced GC animals, cell models, and GC patients. In addition, the number of M2 macrophages was increased in MNU-induced GC mice. Conclusion: Reducing CD14 expression may increase the survival rate of GC patients through the modulation of immune responses. The complex mechanism of CD14's influence on prognosis deserves further investigation.

Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.

IgA nephropathy (IgAN) is a chronic glomerular disease characterized by the deposition of IgA antibodies in the kidney's mesangium. Its pathogenesis involves genetic, immune, and environmental factors, particularly within the mucosal immune system and gut microbiota. Immune cells play a central role in mediating these processes, which this study investigates using Mendelian Randomization (MR) to explore causal relationships among gut microbiota, inflammatory markers, blood cells, and immune cells in IgAN pathogenesis. We conducted a two-sample MR analysis using Genome-Wide Association Study (GWAS) summary data to assess the causal effects of gut microbiota, inflammatory markers, and blood cell traits on IgAN. Data sources included the FinnGen dataset for IgAN and relevant GWAS datasets for immune traits, blood cells, and inflammatory markers. Inverse variance weighting (IVW) was the primary MR method, supported by sensitivity analyses. We particularly examined the mediation effect of immune cells on these exposures' influence on IgAN. Significant associations were found between several factors and IgAN. Gut microbiota traits, such as Firmicutes E and Sporomusales, increased IgAN risk, while Citrobacter A and Herbinix reduced it. Inflammatory markers, including Interleukin-10 and Fibroblast Growth Factor 23, promoted IgAN onset. Blood cell traits like red blood cell perturbation response increased risk, while monocyte perturbation response was protective. Immune traits played a key mediating role, with Transitional %B cells reducing IgAN risk and CD28- CD25 +  + CD8br %T cells increasing it. This study highlights the pivotal mediating role of immune cells in the interactions between gut microbiota, inflammatory markers, and IgAN risk. These findings identify potential biomarkers and therapeutic targets, providing new insights into the immune mechanisms underlying IgAN and opportunities for intervention.

Mast cell tumours (MCTs) are the most frequent cutaneous neoplasia of the dog, and they have very variable biological behaviour and survival times. Surgery is still the best treatment, and despite the several adjuvant therapies described, many cases are very aggressive and resistant to these treatments making it urgent to find new therapeutic targets. Nowadays, immunotherapy targeting immune checkpoints has been described as a complementary treatment for several human cancers, but it is still very scarcely studied in veterinary medicine. Therefore, this study aimed to investigate the expression of the checkpoint proteins programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) to evaluate their potential as therapeutic targets for MCT. Through immunohistochemical study, it was analysed the expression of PD-L1 and CTLA-4 in 74 MCT cases from the archive of the Veterinary Pathology Laboratory of the University of Porto (LabPatVet). Tumour size, histological grade, ki-67 proliferation index, mitotic count and presence of metastatic disease were also assessed. Most of the cases expressed both immune checkpoints in neoplastic cells. There was a statistically significant inverse association between the expression of CTLA-4 and MCT grade (p < 0,001) and mitotic count (p < 0.001). PD-L1 was significantly and negatively related to HG (p = 0.004), and tumour size (р = 0.014). Tumour size, histological grade and mitotic count were positively associated with metastatic disease. Additionally, it was observed that the expression of PD-L1 and CTLA-4 was interrelated (p < 0.001). This study demonstrated that MCT cells express both PD-L1 and CTLA-4 and that their expression was associated with MCT prognostic factors.

Synthetic RNA devices are engineered to control gene expression and offer great potential in both biotechnology and clinical applications. Here, we present multidisciplinary structural and biochemical data for a tetracycline (Tc)-responsive RNA device (D43) in both ligand-free and bound states, providing a structure-dynamical basis for signal transmission. Activation of self-cleavage is achieved via ligand-induced conformational and dynamical changes that stabilize the elongated bridging helix harboring the communication module, which drives proper coordination of the catalytic residues. We then show the utility of CRISPR-integrated D43 in EL4 lymphocytes to regulate programmed cell death protein 1 (PD-1), a key receptor of immune checkpoints. Treatment of these cells with Tc showed a dose-dependent reduction in PD-1 by immunostaining and a decrease in messenger RNA levels by quantitative PCR as compared with wild type. PD-1 expression was recoverable upon removal of Tc. These results provide mechanistic insight into RNA devices with potential for cancer immunotherapy or other applications.

Despite the success of immune checkpoint blockade, a lack of understanding of the hepatocellular carcinoma (HCC) immune microenvironment impedes its development.

We aim to elucidate the essential function of E-twenty-six-specific sequence variant 5 (ETV5) in regulating the immune microenvironment in HCC.

Humanised mouse models, murine orthotopic models and diethylnitrosamine/carbon tetrachloride (DEN/CCl4)-induced HCC models were used to examine the function of ETV5. The downstream targets of ETV5 were screened using chromatin immunoprecipitation sequencing, CUT&Tag and RNA sequencing. Immune cells were examined using flow cytometry and immunofluorescence. S100 calcium-binding protein A9 (S100A9) was targeted by neutralising antibodies.

Overexpression of ETV5 in HCC cells facilitated HCC metastasis and immune escape by recruiting and enhancing the immunosuppressive capabilities of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, ETV5 transactivated programmed death ligand 1 (PD-L1) and S100A9 expression. Inhibition of S100A9 or myeloid-specific knockout of toll-like receptor 4 (TLR4)/receptor for advanced glycation endproducts (RAGE), the receptors of S100A9, impeded ETV5-induced PMN-MDSC recruitment. Meanwhile, S100A9 within the tumour microenvironment elevated ETV5 expression via the extracellular signal-regulated kinase (ERK)/nuclear factor-kappa B pathway. Additionally, ETV5 transcriptionally upregulated PD-L1 in MDSCs as well, thereby augmenting their immunosuppressive functions. Myeloid-specific Etv5 knockout attenuated HCC progression. We developed monoclonal neutralising-S100A9 antibodies that effectively inhibited ETV5-mediated PMN-MDSC infiltration. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy significantly suppressed ETV5-mediated HCC progression.

ETV5 facilitates HCC progression and metastasis by promoting the recruitment, infiltration and activation of PMN-MDSCs. Synergistic application of anti-S100A9 or TLR4/RAGE inhibitors with anti-PD-L1 therapy holds great promise as an effective combinational treatment strategy for ETV5-positive HCC.

The increased expression of programmed cell death ligand 1 (PD-L1) on a subset of immune cells in the peripheral blood has been frequently observed in patients with cancer, suggesting a relationship with PD-L1 expression in tumor tissues. In this study, we investigated the mechanisms underlying PD-L1 expression on various types of immune cells in the peripheral blood of patients with cancer.

PD-L1 expression on various immune cell populations was analyzed in peripheral blood mononuclear cells of 112 patients with non-small cell lung cancer (NSCLC) using flow cytometry. A mouse model of X-ray-induced acute thrombocytopenia was used to investigate the relationship between thrombopoiesis and PD-L1-expressing platelet generation. The clinical significance of PD-L1-expressing platelets was analyzed in a cohort of patients with stage IV NSCLC who received a combination of anti-programmed cell death 1 (PD-1) therapy and chemotherapy.

All immune cell populations, including monocytes, T cells, B cells, and NK cells, showed higher PD-L1 expression in patients with cancer than in healthy controls. However, this increased frequency of PD-L1-expressing cells was not attributed to the expression of the cells themselves. Instead, it was entirely dependent on the direct interaction of the cells with PD-L1-expressing platelets. Notably, the platelet-dependent acquisition of PD-L1 on circulating immune cells of patients with lung cancer was observed in various other cancer types and was mechanistically associated with a surge in thrombopoiesis, resulting in the increased production of PD-L1-expressing reticulated platelets. Clinically, patients with enhanced thrombopoiesis and concurrently high PD-L1-expressing platelets exhibited a better response to anti-PD-1 therapy.

These findings highlight the role of tumor-associated thrombopoiesis in generating PD-L1-expressing platelets that may serve as a resource for PD-L1-positive cells in the circulation and act as a predictive biomarker for anti-PD-1/PD-L1 therapy.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths globally, with poor prognosis due to late diagnosis and limited treatment options. In this study, we evaluated the expression of ectonucleoside triphosphate diphosphohydrolase 8 (ENTPD8) in HCC tissues and its clinical significance. Immunohistochemistry, The Cancer Genome Atlas (TCGA) data, and single-cell expression analysis revealed reduced ENTPD8 levels in liver cancer compared to adjacent tissues, with ENTPD8 primarily expressed in tumor cells within the tumor tissue. In vitro assays demonstrated that ENTPD8 inhibits HCC cell proliferation, invasion, and migration. Mechanistically, ENTPD8 regulates programmed death-ligand 1 (PD-L1) expression through miR-214-5p modulation. In vivo, ENTPD8 overexpression combined with anti-PD-L1 treatment enhanced therapeutic efficacy in HCC mouse models. These findings suggest that ENTPD8 may serve as a prognostic marker and therapeutic target for HCC, offering potential strategies for improving treatment outcomes.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by recurrent inflammatory relapses and neurodegeneration. Myeloid cells play a critical role in shaping the inflammatory environment and influencing disease progression. Here, we demonstrate that activation of the Wnt signaling pathway reprograms myeloid cells into an immunoregulatory phenotype, leading to reduced neuroinflammation and disease severity. Using both experimental autoimmune encephalomyelitis (EAE) and human-derived myeloid cells, we show that Wnt agonist treatment promotes the expression of inhibitory molecules such as PD-L1 and PD-L2, suppressing pro-inflammatory responses. In the chronic and relapsing-remitting EAE models, Wnt activation significantly reduced disease severity, immune cell infiltration into the CNS, and pathogenic T cell responses. Notably, in relapsing-remitting EAE, Wnt treatment prevented new relapses in a PD-L1-dependent manner, highlighting the crucial role of myeloid cell-mediated immune regulation. These findings reveal a previously unrecognized role for Wnt signaling in myeloid cell immunoregulation and suggest that targeting this pathway could provide a novel therapeutic strategy for MS and other autoimmune diseases.

Cancer cells adapt to harsh environmental conditions by inducing the Unfolded Protein Response (UPR), of which ERO1A is a mediator. ERO1A aids protein folding by acting as a protein disulfide oxidase, and under cancer-related hypoxia conditions, it favors the folding of angiogenic VEGFA, leading tumor cells to thrive and spread. The upregulation of ERO1A in cancer cells, oppositely to the dispensability of ERO1A activity in healthy cells, renders ERO1A a perfect target for cancer therapy. Here, we report the upregulation of ERO1A in a cohort of aggressive triple-negative breast cancer (TNBC) patients in which ERO1A levels correlate with a higher risk of breast tumor recurrence and metastatic spread. For ERO1A target validation and therapy in TNBC, we designed new ERO1A inhibitors in a structure-activity campaign of the prototype EN460. Cell-based screenings showed that the presence of the Micheal acceptor in the compound is necessary to engage the cysteine 397 of ERO1A but not sufficient to set out the inhibitory effect on ERO1A. Indeed, the ERO1 inhibitor must adopt a non-coplanar rearrangement within the ERO1A binding site. I2 and I3, two new EN460 analogs with different phenyl-substituted moieties, efficiently inhibited ERO1A, blunting VEGFA secretion. Accordingly, in vitro assays to measure ERO1A engagement and inhibition confirmed that I2 and I3 bind ERO1A and restrain its activity with a IC50 in a low micromolar range. EN460, I2 and I3 triggered breast cancer cytotoxicity while specifically inhibiting ERO1A in a dose-dependent manner. I2 more efficiently impaired cancer-relevant features such as VEGFA secretion and related cell migration. I2 also acted on the tumor microenvironment and viability of xenografts and syngeneic TNBC. Thus, small molecule-mediated ERO1A pharmacological inhibition is feasible and promises to lead to effective therapy for the still incurable TNBC.

Pyroptosis, an excellent form of immunogenic cell death that can effectively activate antitumor immune responses, is attracting considerable interest as a promising approach for cancer immunotherapy. Immunogenic pyroptosis can recruit and stimulate dendritic cells to provoke further activation and tumor infiltration of T cells by releasing danger-associated molecular patterns, thus improving the tumor response to PD-1/PD-L1 checkpoint blockade immunotherapy. Here, we report the discovery of a bifunctional photosensitizer Nile Violet that can simultaneously trigger caspase-3/GSDME-mediated immunogenic pyroptosis and PD-L1 downregulation for cancer photoimmunotherapy. It was shown that this synergistic therapeutic strategy significantly inhibited tumor growth by triggering a systemic antitumor immune response. This work highlights the potential of inducing immunogenic pyroptosis and PD-L1 downregulation for synergistic tumor ablation via a single agent.

Colorectal cancer (CRC) is a prevalent and highly malignant tumor with a limited response to immune checkpoint inhibitor-based immunotherapy. There is an urgent need for novel immunomodulatory agents to enhance the immunotherapeutic response in CRC. Hedyotis diffusa, known for its immunomodulatory properties, has long been utilized as an adjunct in cancer treatment, positioning it as a potential source for discovering new tumor immunomodulators. In this study, we identified a polysaccharide derived from Hedyotis diffusa (HDP), comprising six monosaccharides: rhamnose, arabinose, galactose, glucose, xylose, and mannose. When combined with PD-1 and CTLA-4 inhibitors, HDP can boost systemic immunity in mice to enhance the effectiveness of immune checkpoint inhibitors in CRC therapy. HDP significantly increases the infiltration of CD4+ and CD8+ T cells into tumor microenvironment and upregulates the expression of key effector molecules derived from cytotoxic T cells. Mechanistic studies reveal that HDP activates the IL-2/IL-2R axis by upregulating IL-2 production and the expression of IL-2 receptor subunits, thereby promoting T cell proliferation. Collectively, this research introduces an innovative strategy to improve the efficacy of tumor immunotherapy by harnessing the immunomodulatory potential of polysaccharides. It also directs a roadmap for developing HDP as a promising immunomodulator for CRC treatment.

Immune checkpoint therapy targeting PD-1/PD-L1 has shown promise in treating tumors, however, its clinical benefits are limited to a subset of gastric cancer (GC) patients. Recent research has highlighted a the correlation between PD-L1 expression and the clinical efficacy of anti-PD-1/PD-L1 therapies. Human cytomegalovirus (HCMV) has been implicated in GC, but its specific role in modulating this disease remains elusive. In this study, we analyzed clinical tissue samples using bioinformatics and real-time quantitative polymerase chain reaction (RT-qPCR). We found that GC tissues infected with HCMV presented higher PD-L1 expression compared to those without virus. Furthermore, we demonstrated that HCMV infection enhances PD-L1 expression in GC cells. Cytotoxicity assays revealed that HCMV modulates cancer immune responses via the PD-1/PD-L1 pathway. Mechanistically, we showed that HCMV activates the PI3K-Akt signaling cascade and modulates PD-L1 expression through its tegument protein UL23. Functionally, increased UL23 expression leads to elevated PD-L1 levels, which diminishes tumor cell sensitivity to T-cell-mediated cytotoxicity and triggers T-cell apoptosis. Additionally, in vivo experiments revealed that UL23-induced PD-L1 upregulation inhibits CD8+ T-cell infiltration and reduces the expression of inflammatory factors in tumor microenvironment, ultimately weakening antitumor immunity. Our findings reveal a novel mechanism whereby HCMV and its tegument protein UL23 contribute to cancer immunosuppression through the regulation of PD-L1 expression. This discovery may serve as a potential therapeutic target for enhancing the efficacy of cancer immunotherapy.