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Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Liver cancer, which is well-known to us as one of human most prevalent malignancies across the globe, poses a significant risk to live condition and life safety of individuals in every region of the planet. It has been shown that immune checkpoint treatment may enhance survival benefits and make a significant contribution to patient prognosis, which makes it a promising and popular therapeutic option for treating liver cancer at the current time. However, there are only a very few numbers of patients who can benefit from the treatment and there also exist adverse events such as toxic effects and so on, which is still required further research and discussion. Fortunately, the clustered regularly interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9) provides a potential strategy for immunotherapy and immune checkpoint therapy of liver cancer. In this review, we focus on elucidating the fundamentals of the recently developed CRISPR/Cas9 technology as well as the present-day landscape of immune checkpoint treatment which pertains to liver cancer. What's more, we aim to explore the molecular mechanism of immune checkpoint treatment in liver cancer based on CRISPR/Cas9 technology. At last, its encouraging and powerful potential in the future application of the clinic is discussed, along with the issues that already exist and the difficulties that must be overcome. To sum up, our ultimate goal is to create a fresh knowledge that we can utilize this new CRISPR/Cas9 technology for the current popular immune checkpoint therapy to overcome the treatment issues of liver cancer. [ABSTRACT FROM AUTHOR]

Protective autophagy is a promising target for antitumor drug exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI rate of 44.2% against 4T1 tumors in vivo and exhibited a rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with an inhibition rate of 49.6% and was obviously more potent than CDDP, which has an inhibition rate of 21.6%. Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of an autophagy inhibitor HCQ endowed the platinum(IV) complex with potent autophagy impairing properties by perturbing the lysosomal function in tumor cells, which promoted apoptosis synergistically with DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in the tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting the immune checkpoint PD-L1 and further increasing CD4+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34. [ABSTRACT FROM AUTHOR]

Background: Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. Methods: In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. Results: CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8+ T cells and conventional CD4+ T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1+CD8+ T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. Conclusions: This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1+CD8+ T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment. [ABSTRACT FROM AUTHOR]

Background: Cancer immunotherapy aims to unleash the immune system's potential against cancer cells, providing sustained relief for tumors responsive to immune checkpoint inhibitors (ICIs). While promising in gastric cancer (GC) trials, the efficacy of ICIs diminishes in the context of peritoneal dissemination. Our objective is to identify strategies to enhance the impact of ICI treatment specifically for cases involving peritoneal dissemination in GC. Methods: The therapeutic efficacy of anti-PD1, CTLA4 treatment alone, or in combination was assessed using the YTN16 peritoneal dissemination tumor model. Peritoneum and peritoneal exudate cells were collected for subsequent analysis. Immunohistochemical staining, flow cytometry, and bulk RNA-sequence analyses were conducted to evaluate the tumor microenvironment (TME). A Janus kinase inhibitor (JAKi) was introduced based on the pathway analysis results. Results: Anti-PD1 and anti-CTLA4 combination treatment (dual ICI treatment) demonstrated therapeutic efficacy in certain mice, primarily mediated by CD8 + T cells. However, in mice resistant to dual ICI treatment, even with CD8 + T cell infiltration, most of the T cells exhibited an exhaustion phenotype. Notably, resistant tumors displayed abnormal activation of the Janus Kinase-Signal Transducer and Activator of Transcription (JAK-STAT) pathway compared to the untreated group, with observed infiltration of macrophages, neutrophils, and Tregs in the TME. The concurrent administration of JAKi rescued CD8 + T cells function and reshaped the immunosuppressive TME, resulting in enhanced efficacy of the dual ICI treatment. Conclusion: Dual ICI treatment exerts its anti-tumor effects by increasing tumor-specific CD8 + T cell infiltration, and the addition of JAKi further improves ICI resistance by reshaping the immunosuppressive TME. [ABSTRACT FROM AUTHOR]

[Display omitted] • CD47 has emerged as a target in cancer immunotherapy. • CD47 is highly expressed in cancers to prevent phagocytosis by phagocytes. • Targeting CD47 has been verified as a promising therapeutic strategy in cancer immunotherapy. • Antibodies and small molecules targeting CD47 exhibited both safety and efficacy in clinical trials. • Formidable challenges of targeting CD47 including anemia can be avoided by targeting the regulators of CD47 or its receptor SIRPα. Immunotherapy has emerged as a novel strategy for cancer treatment following surgery, radiotherapy, and chemotherapy. Immune checkpoint blockade and Chimeric antigen receptor (CAR)-T cell therapies have been successful in clinical trials. Cancer cells evade immune surveillance by hijacking inhibitory pathways via overexpression of checkpoint genes. The Cluster of Differentiation 47 (CD47) has emerged as a crucial checkpoint for cancer immunotherapy by working as a "don't eat me" signal and suppressing innate immune signaling. Furthermore, CD47 is highly expressed in many cancer types to protect cancer cells from phagocytosis via binding to SIRPα on phagocytes. Targeting CD47 by either interrupting the CD47-SIRPα axis or combing with other therapies has been demonstrated as an encouraging therapeutic strategy in cancer immunotherapy. Antibodies and small molecules that target CD47 have been explored in pre- and clinical trials. However, formidable challenges such as the anemia and palate aggregation cannot be avoided because of the wide presentation of CD47 on erythrocytes. This review summarizes the current knowledge on the regulation and function of CD47, and provides a new perspective for immunotherapy targeting CD47. It also highlights the clinical progress of targeting CD47 and discusses challenges and potential strategies. This review provides a comprehensive understanding of targeting CD47 in cancer immunotherapy, it also augments the concept of combination immunotherapy strategies by employing both innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Aberrant glycosylation recently emerged as an unmissable hallmark of cancer progression in many cancers. In melanoma, there is growing evidence that the tumour 'glycocode' plays a major role in promoting cell proliferation, invasion, migration, but also dictates the nature of the immune infiltrate, which strongly affects immune cell function, and clinical outcome. Aberrant glycosylation patterns dismantle anti‐tumour defence through interactions with lectins on immune cells, which are crucial to shape anti‐tumour immunity but also to trigger immune evasion. The glycan/lectin axis represents a new immune subversion pathway that is exploited by melanoma to hijack immune cells and escape from immune control. In this review, we describe the glycosylation features of melanoma tumour cells, and further gather findings related to the role of glycosylation in melanoma tumour progression, deciphering in detail its impact on immunity. We also depict glycan‐based strategies aiming at restoring a functional anti‐tumour response in melanoma patients. Glycans/lectins emerge as key immune checkpoints with promising translational properties. Exploitation of these pathways could reshape potent anti‐tumour immunity while impeding immunosuppressive circuits triggered by aberrant tumour glycosylation patterns, holding great promise for cancer therapy. [ABSTRACT FROM AUTHOR]

Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16HHDII/DR1 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled. [ABSTRACT FROM AUTHOR]

Context Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with poor prognosis in advanced stages. While therapies targeting the checkpoint molecules programmed cell death 1 (PD-1), its ligand PD-L1, and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have revolutionized treatment in many cancers, the results in ACCs were heterogeneous. Objective Their expression in ACC has not been systematically studied and might explain the variable response to immune checkpoint inhibitors. Methods The expression of PD-1, PD-L1 and CTLA-4 was examined in 162 tumor samples from 122 patients with ACC by immunohistochemistry (threshold of >1%) and correlated with tumoral T lymphocyte infiltration and clinical endpoints. Finally, univariate and multivariate analyses of progression-free and overall survival were performed. Results PD-1 and PD-L1 were expressed in 26.5% and 24.7% of samples, respectively, with low expression in most tumor samples (median positive cells: 2.1% and 21.7%). In contrast, CTLA-4 expression was observed in 52.5% of ACC with a median of 38.4% positive cells. Positive PD-1 expression was associated with longer progression-free survival (HR 0.50, 95% CI 0.25-0.98, P =.04) even after considering prognostic factors. In contrast, PD-L1 and CTLA-4 did not correlate with clinical outcome. Additionally, PD-1 and PD-L1 expression correlated significantly with the amount of CD3+, CD4+, FoxP3+, and CD8+ T cells. Conclusion The heterogeneous expression of PD1, PD-L1, and CTLA-4 in this large series of well-annotated ACC samples might explain the heterogeneous results of the immunotherapies in advanced ACC. In addition, PD-1 expression is a strong prognostic biomarker that can easily be applied in routine clinical care and histopathological assessment. [ABSTRACT FROM AUTHOR]

The activation of cyclic GMP‐AMP (cGAMP) synthase (cGAS) and its adaptor, stimulator of interferon genes (STING), is known to reprogram the immunosuppressive tumor microenvironment for promoting antitumor immunity. To enhance the efficiency of cGAS‐STING pathway activation, macrophage‐selective uptake, and programmable cytosolic release are crucial for the delivery of STING agonists. However, existing polymer‐ or lipid‐based delivery systems encounter difficulty in integrating multiple functions meanwhile maintaining precise control and simple procedures. Herein, inspired by cGAS being a natural DNA sensor, a modularized DNA nanodevice agonist (DNDA) is designed that enable macrophage‐selective uptake and programmable activation of the cGAS‐STING pathway through precise self‐assembly. The resulting DNA nanodevice acts as both a nanocarrier and agonist. Upon local administration, it demonstrates the ability of macrophage‐selective uptake, endosomal escape, and cytosolic release of the cGAS‐recognizing DNA segment, leading to robust activation of the cGAS‐STING pathway and enhanced antitumor efficacy. Moreover, DNDA elicits a synergistic therapeutic effect when combined with immune checkpoint blockade. The study broadens the application of DNA nanotechnology as an immune stimulator for cGAS‐STING activation. [ABSTRACT FROM AUTHOR]

Summary Natural killer (NK) cells are innate immune effectors whose functions rely on receptors binding cytokines, recognizing self‐molecules, or detecting danger signals expressed by virus‐infected or tumor cells. The potent cytotoxic potential makes NK cells promising candidates for cancer immunotherapy. To enhance their activity strategies include cytokine administration, blocking of immune checkpoints, and designing of antibody‐based NK cell engagers (NKCEs). NKCEs represent a cutting‐edge approach to cancer therapy: they strengthen the NK‐to‐target cell interactions and optimize tumor killing, possibly overcoming the immunosuppressive tumor microenvironment. NK cells belong to the innate lymphoid cells (ILCs) and are categorized into different subsets also including cells with a memory‐like phenotype: this complexity needs to be explored in the context of cancer immunotherapy, particularly when designing NKCEs. Two strategies to enhance NK cell activity in cancer patients can be adopted: activating patients' own NK cells versus the adoptive transfer of ex vivo activated NK cells. Furthermore, the capability of NKCEs to activate γδ T cells could have a significant synergistic effect in immunotherapy. [ABSTRACT FROM AUTHOR]

The EphA family belongs to a large group of membrane receptor tyrosine kinases. Emerging evidence indicates that the EphA family participates in tumour occurrence and progression. Nonetheless, the expression patterns and prognostic values of the nine EphAs in non-small cell lung cancer (NSCLC) have rarely been studied before. In the current study, we comprehensively analysed the expression and prognostic role of EphA family members by different means. The Cancer Genome Atlas and Gene Expression Profiling Interactive Analysis databases were used to investigate the expression of EphAs in NSCLC. The cBioPortal database was applied to analyse the prognostic values and genetic mutations of EphAs.We discovered that the expression of EphA10 was significantly higher in NSCLC tissues than in adjacent noncancerous tissues, and survival analyses showed that a higher level of EphA10 predicted poor prognosis. Further exploration into the role of EphA10 by ESTIMATE, CIBERSORT, and ssGSEA analysis found that it was also related to immune infiltration and higher expression of targets of ICI targets. In conclusion, this study revealed that among the EphA family members, EphA10 played an oncogenic role and was a promising biomarker for poor prognosis and better immunotherapy response in NSCLC. [ABSTRACT FROM AUTHOR]

Background: Belzutifan, a hypoxia-inducible factor 2a inhibitor, showed clinical activity in clear-cell renal-cell carcinoma in early-phase studies. Methods: In a phase 3, multicenter, open-label, active-controlled trial, we enrolled participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies and randomly assigned them, in a 1:1 ratio, to receive 120 mg of belzutifan or 10 mg of everolimus orally once daily until disease progression or unacceptable toxic effects occurred. The dual primary end points were progression-free survival and overall survival. The key secondary end point was the occurrence of an objective response (a confirmed complete or partial response). Results: A total of 374 participants were assigned to belzutifan, and 372 to everolimus. At the first interim analysis (median follow-up, 18.4 months), the median progression-free survival was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (two-sided P = 0.002, which met the prespecified significance criterion). A confirmed objective response occurred in 21.9% of the participants (95% confidence interval [CI], 17.8 to 26.5) in the belzutifan group and in 3.5% (95% CI, 1.9 to 5.9) in the everolimus group (P<0.001, which met the prespecified significance criterion). At the second interim analysis (median follow-up, 25.7 months), the median overall survival was 21.4 months in the belzutifan group and 18.1 months in the everolimus group; at 18 months, 55.2% and 50.6% of the participants, respectively, were alive (hazard ratio for death, 0.88; 95% CI, 0.73 to 1.07; two-sided P = 0.20, which did not meet the prespecified significance criterion). Grade 3 or higher adverse events of any cause occurred in 61.8% of the participants in the belzutifan group (grade 5 in 3.5%) and in 62.5% in the everolimus group (grade 5 in 5.3%). Adverse events led to discontinuation of treatment in 5.9% and 14.7% of the participants, respectively. Conclusions: Belzutifan showed a significant benefit over everolimus with respect to progression-free survival and objective response in participants with advanced clear-cell renal-cell carcinoma who had previously received immune checkpoint and antiangiogenic therapies. Belzutifan was associated with no new safety signals. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; LITESPARK-005 ClinicalTrials.gov number, NCT04195750.). [ABSTRACT FROM AUTHOR]

Skin‐resident antigen‐presenting cells (APC) play an important role in maintaining peripheral tolerance via immune checkpoint proteins and induction of T regulatory cells (Tregs). However, there is a lack of knowledge on how to expand or recruit immunoregulatory cutaneous cells without causing inflammation. Here, it is shown that administration of a non‐coding single‐stranded oligonucleotide (ssON) leads to CCR2‐dependent accumulation of CD45+CD11b+Ly6C+ cells in the skin that express substantial levels of PD‐L1 and ILT3. Transcriptomic analyses of skin biopsies reveal the upregulation of key immunosuppressive genes after ssON administration. Functionally, the cutaneous CD11b+ cells inhibit Th1/2/9 responses and promote the induction of CD4+FoxP3+ T‐cells. In addition, ssON treatment of imiquimod‐induced inflammation results in significantly reduced Th17 responses. It is also shown that induction of IL‐10 production in the presence of cutaneous CD11b+ cells isolated after ssON administrations is partly PD‐L1 dependent. Altogether, an immunomodulatory ssON is identified that can be used therapeutically to recruit cutaneous CD11b+ cells with the capacity to dampen Th cells. [ABSTRACT FROM AUTHOR]

In vitro models coupled with multimodal approaches are needed to dissect the dynamic response of local tumor immune microenvironment (TIME) to immunotherapy. Here the patient‐derived primary lung cancer organoids (pLCOs) are generated by isolating tumor cell clusters, including the infiltrated immune cells. A function‐associated single‐cell RNA sequencing (FascRNA‐seq) platform allowing both phenotypic evaluation and scRNA‐seq at single‐organoid level is developed to dissect the TIME of individual pLCOs. The analysis of 171 individual pLCOs derived from seven patients reveals that pLCOs retain the TIME heterogeneity in the parenchyma of parental tumor tissues, providing models with identical genetic background but various TIME. Linking the scRNA‐seq data of individual pLCOs with their responses to anti‐PD‐1 (αPD‐1) immune checkpoint blockade (ICB) allows to confirm the central role of CD8+ T cells in anti‐tumor immunity, to identify potential tumor‐reactive T cells with a set of 10 genes, and to unravel the factors regulating T cell activity, including CD99 gene. In summary, the study constructs a joint phenotypic and transcriptomic FascRNA‐seq platform to dissect the dynamic response of local TIME under ICB treatment, providing a promising approach to evaluate novel immunotherapies and to understand the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Lung squamous cell carcinoma (LUSC) is a malignancy with limited therapeutic options. Immunogenic cell death (ICD) has the potential to enhance the efficacy of cancer therapy by triggering immune responses. We aimed to explore the potential of ICD‐based classification in predicting prognosis and response to immunotherapy for LUSC. RNA‐seq information and clinical data of LUSC patients were obtained from The Cancer Genome Atlas (TCGA) dataset. ICD‐related gene expressions in LUSC samples were analyzed by consensus clustering. Subsequently, differentially expressed genes (DEGs) between different ICD‐related subsets were analyzed. Tumor mutation burden, immune cell infiltration, and survival analyses were conducted between different ICD subsets. Finally, an ICD‐related risk signature was constructed and evaluated in LUSC patients, and the immunotherapy responses based on the gene expressions were also forecasted. ICD‐high and ICD‐low groups were defined, and 1466 DEGs were identified between the two subtypes. These DEGs were mainly enriched in collagen‐containing extracellular matrix, cytokine–cytokine receptor interaction, the PI3K‐Akt signaling pathway, and neuroactive ligand–receptor interaction. Furthermore, the ICD‐low group exhibited a favorable prognosis, enhanced TTN and MUC16 mutation frequencies, increased infiltrating immune cells, and downregulated immune checkpoint expressions. Furthermore, we demonstrated that an ICD‐related model (based on CD4, NLRP3, NT5E, and TLR4 genes) could forecast the prognosis of LUSC, and ICD risk scores were lower in the responder group. In summary, the predicted values of ICD‐related genes (CD4, NLRP3, NT5E, and TLR4) for the prognosis and response to immunotherapy in LUSC were verified in the study, which benefits immunotherapy‐based interventions for LUSC patients. [ABSTRACT FROM AUTHOR]

Background: In the past few decades, researchers have made promising progress, including the development of immune checkpoint inhibitors (ICIs) in the therapy of bladder cancer (BLCA). Existing studies mainly focus on single immune checkpoint inhibitors but lack relevant studies on the gene expression profiles of multiple immune checkpoints. Methods: RNA-sequencing profiling data and clinical information of BLCA patients and normal human bladder samples were acquired from the Cancer Genome Atlas and Gene Expression Omnibus databases and analyzed to identify different expression profiles of immune checkpoint genes (ICGs) after consensus clustering analysis. Based on the 526 intersecting differentially expressed genes, the LASSO Cox regression analysis was utilized to construct the ICG signature. Results: According to the expression of ICGs, BLCA patients were divided into three subtypes with different phenotypic and mechanistic characteristics. Furthermore, the developed ICG signature were independent predictors of outcome in BLCA patients, and was correlated with the immune infiltration, the expression of ICGs and chemotherapeutic effect. Conclusions: This study systematically and comprehensively analyzed the expression profile of immune checkpoint genes, and established the ICG signature to investigate the differences in ICGs expression and tumor immune microenvironment, which will help risk stratification and accelerate precision medicine. Finally, we identified KRT23 as the most critical model gene, and highlighted KRT23 as a potential target to enhance immunotherapy against BLCA. [ABSTRACT FROM AUTHOR]

Background: Prion protein gene (PRNP) is widely expressed in a variety of tissues. Although the roles of PRNP in several cancers have been investigated, no pancancer analysis has revealed its relationship with tumorigenesis and immunity. Methods: Comprehensive analyses were conducted on The Cancer Genome Atlas (TCGA) Pan-Cancer dataset from the University of California Santa Cruz (UCSC) database to determine the expression of PRNP and its potential prognostic implications. Immune infiltration and enrichment analysis methods were used to ascertain correlations between PRNP expression levels, tumor immunity, and immunotherapy. Additionally, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) methods were employed to examine possible signaling pathways involving PRNP. In vitro experiments using CCK-8 assay, Wound healing assay, and Transwell assay to detect the effect of Cellular prion protein (PrPC) on proliferation, migration, and invasion in colorectal cancer (CRC) cells. The expression levels of epithelial-mesenchymal transition (EMT)-related proteins (N-cadherin, E-cadherin, Vimentin and Snail) were detected by western blot. Results: Among most cancer types, PRNP is expressed at high levels, which is linked to the prognosis of patients. PRNP expression is strongly associated with immune infiltrating cells, immunosuppressive cell infiltration and immune checkpoint molecules. In addition to tumor mutation burden (TMB), substantial correlations are detected between PRNP expression and microsatellite instability (MSI) in several cancers. In vitro cell studies inferred that PrPC enhanced the proliferation, migration, invasion, and EMT of CRC cells. Conclusion: PRNP serves as an immune-related prognostic marker that holds promise for predicting outcomes related to CRC immunotherapy while simultaneously promoting cell proliferation, migration, and invasion activities. Furthermore, it potentially plays a role in governing EMT regulation within CRC. [ABSTRACT FROM AUTHOR]

Background: The newest method of treatment for patients with NSCLC (non-small cell lung cancer) is immunotherapy directed at the immune checkpoints PD-1 (Programmed Cell Death 1) and PD-L1 (Programmed Cell Death Ligand 1). PD-L1 is the only validated predictor factor for immunotherapy efficacy, but it is imperfect. Some patients do not benefit from immunotherapy and may develop primary or secondary resistance. This study aimed to assess the intestinal resistome composition of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors in the context of clinical features and potentially new prediction factors for assessing immunotherapy efficacy. Methods: The study included 30 advanced NSCLC patients, 19 (57%) men and 11 (33%) women treated with first- or second-line immunotherapy (nivolumab, pembrolizumab or atezolizumab). We evaluated the patient's gut resistome composition using the high sensitivity of targeted metagenomics. Results: Studies have shown that resistome richness is associated with clinical and demographic factors of NSCLC patients treated with immunotherapy. Smoking seems to be associated with an increased abundance of macrolides, lincosamides, streptogramins and vancomycin core resistome. The resistome of patients with progression disease appears to be more abundant and diverse, with significantly higher levels of genomic markers of resistance to lincosamides (InuC). The resistance genes InuC, msrD, ermG, aph(6), fosA were correlated with progression-free survival or/and overall survival, thus may be considered as factors potentially impacting the disease. Conclusion: The results indicate that the intestinal resistome of NSCLC patients with immune checkpoint inhibitors treatment differs depending on the response to immunotherapy, with several distinguished markers. Since it might impact treatment efficacy, it must be examined more deeply. [ABSTRACT FROM AUTHOR]

Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death worldwide. surgery, transarterial chemoembolization (TACE), systemic therapy, local ablation therapy, radiotherapy, and targeted drug therapy with agents such as sorafenib. However, the tumor microenvironment of liver cancer has a strong immunosuppressive effect. Therefore, new treatments for liver cancer are still necessary. Immune checkpoint molecules, such as programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen-4 (CTLA-4), along with high levels of immunosuppressive cytokines, induce T cell inhibition and are key mechanisms of immune escape in HCC. Recently, immunotherapy based on immune checkpoint inhibitors (ICIs) as monotherapy or in combination with tyrosine kinase inhibitors, anti-angiogenesis drugs, chemotherapy agents, and topical therapies has offered great promise in the treatment of liver cancer. In this review, we discuss the latest advances in ICIs combined with targeted drugs (targeted-immune combination) and other targeted-immune combination regimens for the treatment of patients with advanced HCC (aHCC) or unresectable HCC (uHCC), and provide an outlook on future prospects. The literature reviewed spans the last five years and includes studies identified using keywords such as "hepatocellular carcinoma," "immune checkpoint inhibitors," "targeted therapy," "combination therapy," and "immunotherapy". [ABSTRACT FROM AUTHOR]

Background: Pancreatic adenocarcinomas (PAADs) often exhibit a "cold" or immunosuppressive tumor milieu, which is associated with resistance to immune checkpoint blockade therapy; however, the underlying mechanisms are incompletely understood. Here, we aimed to improve our understanding of the molecular mechanisms occurring in the tumor microenvironment and to identify biomarkers, therapeutic targets, and potential drugs to improve PAAD treatment. Methods: Patients were categorized according to immunologically hot or cold PAAD subtypes with distinct disease outcomes. Cox regression and weighted correlation network analysis were performed to construct a novel gene signature, referred to as 'Downregulated in hot tumors, Prognostic, and Immune-Related Genes' (DPIRGs), which was used to develop prognostic models for PAAD via machine learning (ML). The role of DPIRGs in PAAD was comprehensively analyzed, and biomarker genes able to distinguish PAAD immune subtypes and predict prognosis were identified by ML. The expression of biomarkers was verified using public single-cell transcriptomic and proteomic resources. Drug candidates for turning cold tumors hot and corresponding target proteins were identified via molecular docking studies. Results: Using the DPIRG signature as input data, a combination of survival random forest and partial least squares regression Cox was selected from 137 ML combinations to construct an optimized PAAD prognostic model. The effects and molecular mechanisms of DPIRGs were investigated by analysis of genetic/epigenetic alterations, immune infiltration, pathway enrichment, and miRNA regulation. Biomarkers and potential therapeutic targets, including PLEC, TRPV1, and ITGB4, among others, were identified, and the cell type-specific expression of the biomarkers was validated. Drug candidates, including thalidomide, SB-431542, and bleomycin A2, were identified based on their ability to modulate DPIRG expression favorably. Conclusions: By combining multiple ML algorithms, we developed a novel prognostic model with excellent performance in PAAD cohorts. ML also proved to be powerful for identifying biomarkers and potential targets for improved PAAD patient stratification and immunotherapy. [ABSTRACT FROM AUTHOR]

In recent years, immunotherapy has emerged as a crucial component of cancer treatment. However, its efficacy remains limited across various cancer types, highlighting unmet needs. Poliovirus receptor-related 2 (PVRL2) and Poliovirus receptor (PVR) are members of the Nectin and Nectin-like Molecules family, known for their role as cell-cell adhesion molecules. With the development of immunotherapy, their involvement in tumor immune mechanisms as immune checkpoint factors has garnered significant attention. PVRL2 and PVR are predominantly expressed on tumor cells and antigen-presenting cells, binding to PVRIG and TIGIT, respectively, which are primarily found on T and NK cells, thereby suppressing antitumor immunity. Notably, gynecological cancers such as ovarian and endometrial cancers exhibit high expression levels of PVRL2 and PVR, with similar trends observed in various other solid and hematologic tumors. Targeting these immune checkpoint pathways offers a promising therapeutic avenue, potentially in combination with existing treatments. However, the immunomodulatory mechanism involving these bindings, known as the DNAM-1 axis, is complex, underscoring the importance of understanding it for developing novel therapies. This article comprehensively reviews the immunomodulatory mechanisms centered on PVRL2 and PVR, elucidating their implications for various cancer types. [ABSTRACT FROM AUTHOR]

Compensation and intracellular storage of PD-L1 may compromise the efficacy of antibody drugs targeting the conformational blockade of PD1/PD-L1 on the cell surface. Alternative therapies aiming to reduce the overall cellular abundance of PD-L1 thus might overcome resistance to conventional immune checkpoint blockade. Here we show by bioinformatics analysis that colon adenocarcinoma (COAD) with high microsatellite instability (MSI-H) presents the most promising potential for this therapeutic intervention, and that overall PD-L1 abundance could be controlled via HSC70-mediated lysosomal degradation. Proteomic and metabolomic analyses of mice COAD with MSI-H in situ unveil a prominent acidic tumor microenvironment. To harness these properties, an artificial protein, IgP β, is engineered using pH-responsive peptidic foldamers. This features customized peptide patterns and designed molecular function to facilitate interaction between neoplastic PD-L1 and HSC70. IgP β effectively reduces neoplastic PD-L1 levels via HSC70-mediated lysosomal degradation, thereby persistently revitalizing the action of tumor-infiltrating CD8 + T cells. Notably, the anti-tumor effect of lysosomal-degradation-based therapy surpasses that of antibody-based immune checkpoint blockade for MSI-H COAD in multiple mouse models. The presented strategy expands the use of peptidic foldamers in discovering artificial protein drugs for targeted cancer immunotherapy. The efficiency of antibody-based immune checkpoint blockades could be compromised by the intracellular accumulation of checkpoint proteins. Here authors show that a pH-responsive artificial protein that targets PD-L1 to lysosomal degradation could achieve superior therapeutic effect compared to anti-PD-L1 treatment in mouse models of high microsatellite instability colon adenocarcinoma. [ABSTRACT FROM AUTHOR]

The combination of radiotherapy/chemoradiotherapy and immune checkpoint blockade can result in poor outcomes in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Here, we show that combining ATR inhibition (ATRi) with radiotherapy (RT) increases the frequency of activated NKG2A+PD-1+ T cells in animal models of HNSCC. Compared with the ATRi/RT treatment regimen alone, the addition of simultaneous NKG2A and PD-L1 blockade to ATRi/RT, in the adjuvant, post-radiotherapy setting induces a robust antitumour response driven by higher infiltration and activation of cytotoxic T cells in the tumour microenvironment. The efficacy of this combination relies on CD40/CD40L costimulation and infiltration of activated, proliferating memory CD8+ and CD4+ T cells with persistent or new T cell receptor (TCR) signalling, respectively. We also observe increased richness in the TCR repertoire and emergence of numerous and large TCR clonotypes that cluster based on antigen specificity in response to NKG2A/PD-L1/ATRi/RT. Collectively, our data point towards potential combination approaches for the treatment of HNSCC. Immune checkpoint blockade can result in good outcomes in patients with metastatic head and neck squamous cell carcinoma (HNSCC), but not those with locally advanced disease. Here, the authors demonstrate that the addition of anti-NKG2A and anti-PD-L1 blockade to ATR inhibition and radiotherapy in the adjuvant setting can induce a robust antitumour immune response in mice. [ABSTRACT FROM AUTHOR]

Pyroptosis is a programmed cell death, which garners increasing attention by relating to immune and therapy response. However, the role of pyroptosis in colorectal cancer (CRC) remains unclear. Our study mainly to explore the role of pyroptosis in CRC. The mRNA expression data and corresponding clinical information of CRC patients were achieved from The Cancer Genome Atlas (TCGA). Pyroptosis-related genes (PRGs) were identified using DESeq2 R package and biological function was analyzed using cluster Profiler R package. A PRGs-based prognosis model was constructed by a univariate Cox and LASSO regression analyses. Then, the affecting of risk signature to clinicopathological characteristics, immune status and infiltrated immune cells, immune checkpoint and chemotherapy sensitivity was analyzed. qRT-PCR and IHC were performed for the expression level of PRGs. Moreover, a nomogram predict model was constructed. Total 57 PRGs were identified between 500 CRC samples and 44 normal samples. Those PRGs mainly enriched in immune-related and pyroptosis-related pathways. GABRD, NADK, TMEM240, RER1, AGRN, UBE2J2, CALML6, PLCH2, TMEM88B have been identified as gene signature and a prognostic model was constructed and validated. CRC patients with high-risk score showed poor survival, high TMB score, high proportion of CD4 + memory T cells, common lymphoid progenitors, cancer associated fibroblasts, mast cells, and neutrophils. The immune checkpoint related genes, CD160, CD200R1, CD244, CD28, CD40LG, CD44, CD48, CD80, CD86, HHLA2, ICOS, IDO1, TIGIT, TNFRSF25, TNFRSF4, TNFRSF9, TNFSF15, TNFSF18 also increased in high-risk score group. CRC patients with high-risk score more sensitive to docetaxel and rapamycin but resistance to gemcitabine and mitomycin. Moreover, a predictive nomogram for 1-, 3-, 5-year for CRC patients was established and validated. In the study, a PRGs-based prognostic model and a predictive model were constructed. These models are effective and robust in prediction the 1-, 3-, and 5-year survival of CRC patients. [ABSTRACT FROM AUTHOR]

Breast cancer is the primary cause of cancer‐related death in women worldwide. Breast cancer subtypes are characterized by different gene expression patterns, which drive their prognostic factors and therapeutic options. Among them, triple‐negative breast cancer (TNBC) is one of the deadliest due to its aggressiveness, high rate of early recurrence and distant metastases, and limited therapeutic options. Despite the recent approval of monoclonal antibodies targeting programmed cell death protein 1 (PD‐1) or its ligand (PD‐L1) for the treatment of TNBC patients with a locally recurrent unresectable or metastatic tumor expressing PD‐L1, their response rate is very modest. It is reported that polymeric nanoparticle (NP)‐based cancer vaccines, co‐entrapping tumor‐associated antigens, Toll‐like receptor ligands and small interfering RNA (siRNA) targeting the expression of the immunosuppressive cytokine transforming growth factor (TGF)‐β1 by dendritic cells, sensitized TNBC to the agonist immune checkpoint OX40, inhibiting tumor growth and increasing overall survival. This anti‐tumor immune‐mediated effect is also observed in a luminal type of mammary cancer similar to human disease. Therefore, these synergistic anticancer effects of αOX40 and the antigen‐specific adaptive immunity induced by nanovaccine‐mediated TGF‐β silencing may guide the development of novel combination regimens able to improve the response rate to this aggressive tumor. [ABSTRACT FROM AUTHOR]

Heterogenous immune responses to checkpoint blockade therapy remain a major challenge to early prediction of treatment efficacy. Current methods of evaluating treatment efficacy in tumors are ineffective in accurately monitoring the disease status after immunotherapy early on. This study reports an immune response monitoring strategy that longitudinally reports on two crucial protease activities involved in T cell‐mediated target cell death, granzyme B (GrzB) and downstream caspase 3 (Casp3), during and after immune checkpoint antibody treatment. Specifically, activatable nanoreporters are engineered to sensitively and selectively capture the activity of GrzB and Casp3 enzymes in tumor cells triggered by cytotoxic T cells in real‐time, providing a direct readout of the tumor response to immune checkpoint inhibitors (ICIs). Furthermore, incorporating 3D tumor‐derived organoids and ex vivo cultures on microfluidic devices with nanoreporters enables high‐throughput screening of various ICIs and their combinations in immunocompetent tumor models. These findings suggest that efficient monitoring of dynamic immunological processes in the tumor microenvironment could help uncover mechanisms associated with ICI response or resistance. It is further anticipated that combining the dual‐sensing nanoreporter with tumor‐derived organoid‐on‐chip technology could lead to an early prediction of treatment outcomes with high fidelity and accelerate the development of optimal treatment in immuno‐oncology. [ABSTRACT FROM AUTHOR]

Background: Thermal ablation is a minimally invasive treatment for non-small cell lung cancer (NSCLC). Aside from causing an immediate direct tumour cell injury, the effects of thermal ablation on the internal microenvironment are unknown. This study aimed to investigate the effects of thermal ablation on the plasma internal environment in patients with NSCLC. Methods: 128 plasma samples were collected from 48 NSCLC (pre [LC] and after thermal ablation [LC-T]) patients and 32 healthy controls (HCs). Olink proteomics and metabolomics were utilized to construct an integrated landscape of the cancer-related immune and inflammatory responses after ablation. Results: Compared with HCs, LC patients exhibited 58 differentially expressed proteins (DEPs) and 479 differentially expressed metabolites (DEMs), which might participate in tumour progression and metastasis. Moreover, 75 DEPs were identified among the HC, LC, and LC-T groups. Forty-eight highly expressed DEPs (eg, programmed death-ligand 1 [PD-L1]) in the LC group were found to be downregulated after thermal ablation. These DEPs had significant impacts on pathways such as angiogenesis, immune checkpoint blockade, and pro-tumour chemotaxis. Metabolites involved in tumour cell survival were associated with these proteins at the expression and functional levels. In contrast, 19 elevated proteins (eg, interleukin [IL]-6) were identified after thermal ablation. These proteins were mainly associated with inflammatory response pathways (NF-κB signalling and tumour necrosis factor signalling) and immune cell activation. Conclusions: Thermal ablation-induced changes in the host plasma microenvironment contribute to anti-tumour immunity in NSCLC, offering new insights into tumour ablation combined with immunotherapy. Trial registration This study was registered on the Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html). ID: ChiCTR2300076517. Registration Date: 2023-10-11. [ABSTRACT FROM AUTHOR]

Background: The activity and number of immune cells in the tumor microenvironment are closely related to the overall survival of patients with hepatocellular carcinoma (HCC). The sex-determining region Y-box 4 (SOX4) gene is abnormally expressed in various tumor tissues and is critical for tumor development. However, the correlation between SOX4 expression in HCC and tumor immunity is unclear. Methods: SOX4 expression was explored using data from The Cancer Genome Atlas, and UALCAN databases. Real-time reverse transcription quantitative and western blotting were used to analyze SOX4 expression in several liver cancer cell lines. Additionally, correlations among SOX4 expression, cancer immune characteristics, and infiltrated immune cell gene marker sets in patients with HCC were analyzed using data from the Tumor Immune Estimation Resource, Gene Expression Profiling Interactive Analysis, and Tumor-Immune System Interactions databases. Moreover, we evaluated SOX4 expression in HCC tissues and the correlation of SOX4 expression with survival rate. Subsequently, noncoding RNAs (ncRNAs) responsible for SOX4 overexpression were identified using expression, correlation, and survival analyses. Results: SOX4 expression was significantly upregulated in HCC and correlated with a poor prognosis. Additionally, SOX4 upregulation in HCC positively correlated with immune cell infiltration, several biomarkers of immune cells, and immune checkpoint expression. Finally, the MCM3AP-AS1/hsa-miR-204-5p axis was identified as the most likely upstream ncRNA-related pathway for SOX4 in HCC. These results indicated that ncRNA-mediated upregulation of SOX4 correlated with the immune infiltration level and poor prognosis in HCC. Our findings provide new directions for the development of novel immunotherapeutic targets for HCC. [ABSTRACT FROM AUTHOR]

Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress--responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eukaryotic translation initiation factor-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PKR-like ER kinase (PERK), a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA-Seq of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen-processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (PD-L1) in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity and that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D. [ABSTRACT FROM AUTHOR]

[Display omitted] Tumor metastasis and recurrence are closely related to immune escape and hypoxia. Chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) can induce immunogenic cell death (ICD), and their combination with immune checkpoint agents is a promising therapeutic strategy. Iron based nanomaterials have received more and more attention, but their low Fenton reaction efficiency has hindered their clinical application. In this study, Fe 3 O 4 -carbon dots complex (Fe 3 O 4 -CDs) was synthesized, which was modified with ferrocenedicarboxylic acid by amide bond, and crosslinked into Fe 3 O 4 -CDs@Fc nano complex. The CDs catalyzed the Fenton reaction activity of Fe 3 O 4 by helping to improve the electron transfer efficiency, extended the reaction pH condition to 7.4. The Fe 3 O 4 -CDs@Fc exhibit exceptional optical activity, achieving a thermal conversion efficiency of 56.43 % under 808 nm light and a photosensitive single-line state oxygen quantum yield of 33 % under 660 nm light. Fe 3 O 4 -CDs@Fc improved intracellular oxygen level and inhibited hypoxia-inducing factor (HIF-1 α) by in-situ oxygen production based on Fenton reaction. The multimodal combination of Fe 3 O 4 -CDs@Fc (CDT/PDT/PTT) strongly induced immune cell death (ICD). The expression of immune-related protein and HIF-1 α was investigated by immunofluorescence method. In vivo, Fe 3 O 4 -CDs@Fc combined with immune checkpoint blocker (antibody PD-L1, αPD-L1) effectively ablated primary tumors and inhibited distal tumor growth. Fe 3 O 4 -CDs@Fc is a promising immune-antitumor drug. [ABSTRACT FROM AUTHOR]

Immune checkpoint therapy has limited efficacy for patients with bone-metastatic castration-resistant prostate cancer (bmCRPC). To improve immunotherapy for bmCRPC, we aimed to identify the mechanism of bmCRPC-induced changes in the immune microenvironment. Among bmCRPC patients, higher levels of a 32-gene M2-like macrophage signature in bone metastasis samples correlated with shorter overall survival. Immunohistochemistry showed that CD206-positive (CD206+) macrophages were enriched in bmCRPC bone biopsy specimens compared with primary tumors or lymph node metastases. In preclinical osteogenic prostate cancer (Pca) xenograft models, CD206+ macrophages were recruited to areas with tumor-induced bone. RNA sequencing (RNAseq) analysis showed higher expression of an M2-like gene signature, with activated canonical and noncanonical Wnt pathways, in tumor-associated macrophages isolated from osteogenic tumors (bone-TAMs) than in TAMs isolated from nonosteogenic tumors (ctrl-TAMs). Mechanistic studies showed that endothelial cells (ECs) that had undergone EC-to-osteoblast (EC-to-OSB) transition, the precursors of tumor-induced OSBs, produced paracrine factors, including Wnts, CXCL14, and lysyl oxidase, which induced M2 polarization and recruited M2-like TAMs to the bone-tumor microenvironment (bone-TME). Bone-TAMs suppressed CD8+ T cells' proliferation and cytolytic activity, and these effects were partially reversed by treating bone-TAMs with Wnt inhibitors. Genetic or pharmacological inhibition of Pca-induced EC-to-OSB transition reduced the levels of M2-like macrophages in osteogenic tumors. Our study demonstrates that Pca-induced EC-to-OSB transition drives immunosuppression in the bone-TME, suggesting that therapies that reduce Pca-induced bone formation may improve immunotherapeutic outcomes for bmCRPC. [ABSTRACT FROM AUTHOR]

Endometrial cancer (UCEC) is one of three major malignant tumors in women. The HOX gene regulates tumor development. However, the potential roles of HOX in the expression mechanism of multiple cell types and in the development and progression of tumor microenvironment (TME) cell infiltration in UCEC remain unknown. In this study, we utilized both the The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database to analyze transcriptome data of 529 patients with UCEC based on 39 HOX genes, combing clinical information, we discovered HOX gene were a pivotal factor in the development and progression of UCEC and in the formation of TME diversity and complexity. Here, a new scoring system was developed to quantify individual HOX patterns in UCEC. Our study found that patients in the low HOX score group had abundant anti-tumor immune cell infiltration, good tumor differentiation, and better prognoses. In contrast, a high HOX score was associated with blockade of immune checkpoints, which enhances the response to immunotherapy. The Real-Time quantitative PCR (RT-qPCR) and Immunohistochemistry (IHC) exhibited a higher expression of the HOX gene in the tumor patients. We revealed that the significant upregulation of the HOX gene in the epithelial cells can activate signaling pathway associated with tumour invasion and metastasis through single-cell RNA sequencing (scRNA-seq), such as nucleotide metabolic proce and so on. Finally, a risk prognostic model established by the positive relationship between HOX scores and cancer-associated fibroblasts (CAFs) can predict the prognosis of individual patients by scRNA-seq and transcriptome data sets. In sum, HOX gene may serve as a potential biomarker for the diagnosis and prediction of UCEC and to develop more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

This review explores the intricate roles of metal ions—iron, copper, zinc, and selenium—in glioma pathogenesis and immune evasion. Dysregulated metal ion metabolism significantly contributes to glioma progression by inducing oxidative stress, promoting angiogenesis, and modulating immune cell functions. Iron accumulation enhances oxidative DNA damage, copper activates hypoxia-inducible factors to stimulate angiogenesis, zinc influences cell proliferation and apoptosis, and selenium modulates the tumor microenvironment through its antioxidant properties. These metal ions also facilitate immune escape by upregulating immune checkpoints and secreting immunosuppressive cytokines. Targeting metal ion pathways with therapeutic strategies such as chelating agents and metalloproteinase inhibitors, particularly in combination with conventional treatments like chemotherapy and immunotherapy, shows promise in improving treatment efficacy and overcoming resistance. Future research should leverage advanced bioinformatics and integrative methodologies to deepen the understanding of metal ion-immune interactions, ultimately identifying novel biomarkers and therapeutic targets to enhance glioma management and patient outcomes. [ABSTRACT FROM AUTHOR]

Although immune checkpoint blockade has shown initial success for various cancers, only a small subset of patients benefits from this therapy. Some chemotherapeutic drugs have been reported to induce antitumor T cell responses, prompting a number of clinical trials on combination chemoimmunotherapy. However, how to achieve potent immune activation with traditional chemotherapeutics in a manner that is safe, effective, and compatible with immunotherapy remains unclear. We show that high-density lipoprotein-mimicking nanodiscs loaded with doxorubicin (DOX), a widely used chemotherapeutic agent, can potentiate immune checkpoint blockade in murine tumor models. Delivery of DOX via nanodiscs triggered immunogenic cell death of cancer cells and exerted antitumor efficacy without any overt off-target side effects. "Priming" tumors with DOX-carrying nanodiscs elicited robust antitumor CD8+ T cell responses while broadening their epitope recognition to tumor-associated antigens, neoantigens, and intact whole tumor cells. Combination chemoimmunotherapy with nanodiscs plus anti-programmed death 1 therapy induced complete regression of established CT26 and MC38 colon carcinoma tumors in 80 to 88% of animals and protected survivors against tumor recurrence. Our work provides a new, generalizable framework for using nanoparticle-based chemotherapy to initiate antitumor immunity and sensitize tumors to immune checkpoint blockade. [ABSTRACT FROM AUTHOR]

Programmed cell death (PCD) is a process that eliminates infected, damaged, or possibly neoplastic cells to sustain homeostatic multicellular organisms. Although long noncoding RNAs (lncRNAs) are involved in various types of PCD and regulate tumor growth, invasion, and migration, the role of PCD-related lncRNAs in bladder cancer still lacks systematic exploration. In this research, we integrated multiple types of PCD as pan-PCD and identified eight pan-PCD-related lncRNAs (LINC00174, HCP5, HCG27, UCA1, SNHG15, GHRLOS, CYB561D2, and AGAP11). Then, we generated a pan-PCD-related lncRNA prognostic signature (PPlncPS) with excellent predictive power and reliability, which performed equally well in the E-MTAB-4321 cohort. In comparison with the low-PPlncPS score group, the high-PPlncPS score group had remarkably higher levels of angiogenesis, matrix, cancer-associated fibroblasts, myeloid cell traffic, and protumor cytokine signatures. In addition, the low-PPlncPS score group was positively correlated with relatively abundant immune cell infiltration, upregulated expression levels of immune checkpoints, and high tumor mutation burden (TMB). Immunogenomic profiles revealed that patients with both low PPlncPS scores and high TMB had the best prognosis and may benefit from immune checkpoint inhibitors. Furthermore, for patients with high PPlncPS scores, docetaxel, staurosporine, and luminespib were screened as potential therapeutic candidates. In conclusion, we generated a pan-PCD-related lncRNA signature, providing precise and individualized prediction for clinical prognosis and some new insights into chemotherapy and immune checkpoint inhibitor therapy for bladder cancer. [ABSTRACT FROM AUTHOR]

Background: Zinc Finger Protein 337 (ZNF337) is a novel Zinc Finger (ZNF) protein family member. However, the roles of ZNF337 in human cancers have not yet been investigated. Methods: In this study, with the aid of TCGA databases, GTEx databases, and online websites, we determined the expression levels of ZNF337 in pan-cancer and its potential value as a diagnostic and prognostic marker for pan-cancer and analyzed the relationship between ZNF337 expression and immune cell infiltration and immune checkpoint genes. We then focused our research on the potential of ZNF337 as a biomarker for diagnostic and prognostic in KIRC (kidney renal clear cell carcinoma) and validated in the E-MTAB-1980 database. Moreover, the expression of ZNF337 was detected through qRT-PCR and Western blotting (WB). CCK-8 experiment, colony formation experiment, and EDU experiment were performed to evaluate cell proliferation ability. Wound healing assay and transwell assay were used to analyze its migration ability. The qRT-PCR and WB were used to detect the expression of ZNF337 in tumor tissues and paracancerous tissues of KIRC patients. Results: The pan-cancer analysis revealed that abnormal ZNF337 expression was found in multiple human cancer types. ZNF337 had a high diagnostic value in pan-cancer and a significant association with the prognosis of certain cancers, indicating that ZNF337 may be a valuable prognostic biomarker for multiple cancers. Further analysis demonstrated that the expression level of ZNF337 displayed significant correlations with cancer-associated fibroblasts, immune cell infiltration, and immune checkpoint genes in many tumors. Additionally, ZNF337 was observed to have a high expression in KIRC. Its expression was significantly associated with poor prognosis [overall survival (OS), disease-specific survival (DSS)], age, TNM stage, histologic grade, and pathologic stage. The high ZNF337 expression was associated with poor prognosis in the E-MTAB-1980 validation cohort. The in vitro experiments suggested that the expression of ZNF337 in KIRC tumor tissues was higher than in adjacent tissues, and ZNF337 knockdown inhibited the proliferation and migration of KIRC cells, whereas overexpression of ZNF337 had the opposite effects. Conclusions: ZNF337 might be an important prognostic and immunotherapeutic biomarker for pan-cancer, especially in KIRC. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockade (ICB) is emerging as an efficient strategy for cancer immunotherapy, which highly relies on the controlled loading and release of immune checkpoints inhibitors. Herein, a responsive DNA hydrogel containing polyvalent aptamers as dual‐target inhibitors is reported to achieve ICB for localized cancer immunotherapy. This DNA hydrogel is constructed by two ultralong DNA chains generated via rolling circle amplification (RCA), which contained two polyvalent aptamers (PD‐1 and CTLA‐4 aptamers), and is loaded with inflammatory‐responsive nanoparticles that encapsulated restriction endonuclease. The DNA hydrogel achieved the specific enrichment of T cells. The restriction endonuclease is specifically released by responding to the inflammatory microenvironment, which subsequently cleaved the DNA hydrogel at the cutting sites of DNA chains. The released PD‐1 and CTLA‐4 aptamers executed the biological functions as immune checkpoint inhibitors, successfully blocking immune checkpoints to activate T cells in tumor sites; as a result, the killing efficacy toward tumor cells is significantly enhanced. In a melanoma tumor‐bearing mouse model, the DNA hydrogel activated the immune response in tumor tissues and showed notable therapeutic efficacy for the inhibition of tumor progression (≈65%). This responsive DNA hydrogel is expected to be a promising formulation for immunotherapeutic medicines. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti‐tumor efficiency of immunotherapy. In this study, an immune‐stimulating polypeptide hydrogel conjugated with an indoleamine‐2,3‐dioxygenase (IDO) inhibitor, 1‐methyl‐D‐tryptophan (D1MT), through a glutathione (GSH)‐responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD‐1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent‐loaded hydrogel elicited effective anti‐tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune‐stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune‐stimulating hydrogel has great potential as a stimuli‐responsive platform for regulating suppressive TME and enhanced anti‐tumor chemo‐immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Programmed Death-Ligand 1 is a well-known immune checkpoint molecule. Recent studies evaluated its expression in different canine cancer types through different laboratory techniques. The present study aims to evaluate the surface membrane protein expression (mPD-L1) by means of flow cytometry (FC) in different canine lymphoma immunophenotypes. Furthermore, in a subset of cases, mRNA and plasmatic soluble protein (sPD-L1) have been assessed in the same patient, and correlations among results from the three analyses investigated. Methods: Samples obtained for diagnostic purpose from untreated dogs with a confirmed lymphoma immunophenotype were included: surface protein was assessed via FC and quantified with median fluorescence index ratio (MFI ratio), gene expression was evaluated by real time quantitative polymerase chain reaction (RT-qPCR) and plasmatic concentration of soluble protein (sPD-L1) measured with ELISA. Statistical analyses were performed to investigate any difference among FC immunophenotypes, updated Kiel cytological classes, and in the presence of blood infiltration. Results: Considering FC, most B-cell lymphomas (BCL) were positive, with higher MFI ratios than other subtypes (81%, median MFI ratio among positive samples = 1.50, IQR 1.21-2.03, range 1.01-3.47). Aggressive T-cell lymphomas had a lower percentage of positive samples (56%) and showed low expression (median MFI ratio in positive samples = 1.14, IQR 1.07-1.32, range 1.02-2.19), while T-zone lymphomas (TZL) were frequently positive (80%) but with low expression (median MFI ratio in positive samples = 1.19, IQR 1.03-1.46, range 1.02-6.03). Cellular transcript and sPD-L1 were detected in all samples, without differences among immunophenotypes. No correlation between results from different techniques was detected, but sPD-L1 resulted significantly increased in FC-negative lymphomas (p = 0.023). Discussion: PD-L1 molecule is involved in canine lymphoma pathogenesis, with differences among immunophenotypes detected by FC. Specifically, BCL have the highest expression and aggressive T-cell lymphomas the lowest, whereas TZL need further investigations. [ABSTRACT FROM AUTHOR]

Transcriptional heterogeneity of tumor-associated macrophages (TAMs) has been investigated in individual cancers, but the extent to which these states transcend tumor types and represent a general feature of cancer remains unclear. We performed pan-cancer single-cell RNA sequencing analysis across nine cancer types and identified distinct monocyte/TAM composition patterns. Using spatial analysis from clinical study tissues, we assessed TAM functions in shaping the tumor microenvironment (TME) and influencing immunotherapy. Two specific TAM clusters (pro-inflammatory and pro-tumor) and four TME subtypes showed distinct immunological features, genomic profiles, immunotherapy responses, and cancer prognosis. Pro-inflammatory TAMs resided in immune-enriched niches with exhausted CD8+ T cells, while pro-tumor TAMs were restricted to niches associated with a T-cell-excluded phenotype and hypoxia. We developed a machine learning model to predict immune checkpoint blockade response by integrating TAMs and clinical data. Our study comprehensively characterizes the common features of TAMs and highlights their interaction with the TME. [ABSTRACT FROM AUTHOR]

Background: Tumor tissues comprise cancer cells and stromal cells, and their interactions form the cancer microenvironment. Therefore, treatments targeting cells other than cancer cells are also actively being developed, and among them, treatment targeting PD-1, an immune checkpoint molecule that is important in tumor immune evasion, has also been indicated for head and neck cancer. PD-L1, a ligand of PD-1, is expressed in both tumor cells and stromal cells, and the scoring system based on the combined positivity rates of both types of cells, the combined positive score (CPS), is used for predicting treatment effect. However, much is unknown regarding the expression of PD-L1. In this study, we histopathologically examined factors controlling the expression of PD-1/PD-L1. This study included 37 patients who underwent resection surgery for tongue squamous cell carcinoma in the Department of Oral and Maxillofacial Surgery at Tokyo Dental College Suidobashi Hospital. The expression levels of PD-L1, α-SMA, and p53 were assessed by immunohistochemical staining. Results: Seven participants had CPS ≥ 20, twenty-four participants had 1 ≤ CPS < 20, and six participants had CPS < 1. The overall positivity rate of α-SMA, a marker for cancer-associated fibroblasts (CAFs), was 27% (10/37 participants), and the positivity rates of α-SMA for the three CPS groups were 85.7% (6/7 participants), 16.7% (4/24 participants), and 0% (0/6 participants), respectively. In addition, the overall positivity rate of p53 was 37.8% (14/37 participants), and the positivity rates of p53 for the three CPS groups were 71.4% (5/7 participants), 37.5% (9/24 participants), and 0% (0/6 participants), respectively. Conclusions: The expression of PD-L1 demonstrated an association with α-SMA and p53 positivity. In addition, compared with the expression of p53, the expression of α-SMA demonstrated a higher association with PD-L1 expression in patients with a high CPS. The abovementioned findings suggest that the interactions between CAFs, cancer cells, and immunocompetent cells may regulate the expression of PD-L1. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) stress exerts significant effects on cell growth, proliferation, migration, invasion, chemoresistance, and angiogenesis in various cancers. However, the impact of ER stress on the outcomes of osteosarcoma patients remains unclear. In this study, we established an ER stress risk model based on The Cancer Genome Atlas (TARGET) osteosarcoma dataset to reflect immune features and predict the prognosis of osteosarcoma patients. Survival analysis revealed significant differences in overall survival among osteosarcoma patients with different ER stress-related risk scores. Furthermore, ER stressrelated risk features were significantly associated with the clinical pathological characteristics of osteosarcoma patients and could serve as independent prognostic indicators. Functional enrichment analysis indicated associations of the risk model with cell chemotaxis, leukocyte migration, and regulation of leukocyte migration. Additionally, the ER stress-related risk model suggested the presence of an immunosuppressive microenvironment and immune checkpoint responses. We validated the significance of 7 ER stress-related genes obtained from LASSO regression analysis through RT-qPCR testing on osteosarcoma samples from a local hospital, and inferred the importance of STC2 based on the literature. Subsequently, IHC experiments using samples from 70 osteosarcoma cases and 21 adjacent tissue samples confirmed differential expression of STC2 between cancer and normal tissues, and explored the gene's expression in pan-cancer and its association with clinical pathological parameters of osteosarcoma. In conclusion, we have proposed an ER stress risk model as an independent prognostic factor and identified STC2 as a novel risk indicator for disease progression, providing a promising direction for further research and treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]

Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1‐deficient mice are resistant to metastasis and further protected by combined immune‐checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF‐β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK‐target cell responses, which is dysregulated and hijacked by tumors during metastatic progression. [ABSTRACT FROM AUTHOR]

Inhibiting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)-mediated immune checkpoint system using an anti-CTLA-4 antibody (Ab) can suppress the growth of various cancers, but the detailed mechanisms are unclear. In this study, we established a monoclonal hepatocellular carcinoma cell line (Hepa1-6 #12) and analyzed the mechanisms associated with anti-CTLA-4 Ab treatment. Depletion of CD4+ T cells, but not CD8+ T cells, prevented anti-CTLA-4 Ab-mediated anti-tumor effects, suggesting dependence on CD4+ T cells. Anti-CTLA-4 Ab treatment resulted in recruitment of interferon-gamma (IFN-g)-producing CD4+ T cells, called T-helper 1 (Th1), into tumors, and neutralization of IFN-g abrogated the anti-tumor effects. Moreover, tumor growth suppression did not require major histocompatibility complex (MHC)-I or MHC-II expression on cancer cells. In vitro studies showed that IFN-g can induce cell cycle arrest and apoptosis in tumor cells. Taken together, these data demonstrate that anti-CTLA-4 Ab can exert its anti-tumor effects through Th1-mediated cell cycle arrest and apoptosis. [ABSTRACT FROM AUTHOR]

Immune checkpoints refer to mechanisms entrusted with the modulation of immune responses in peripheral tissues and are required for minimising collateral damage. Immune checkpoint inhibitors (ICPi) work through numerous pathways, including the anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), anti-PD-1 (programmed cell death protein 1) and the PD-L1 (protein cell death protein-ligand-1) pathways. They are proving to be an exciting therapeutic avenue in the attempt to activate anti-tumour activity. Ipilimumab is a fully human monoclonal antibody working on the anti-CTLA-4 pathway, while nivolumab and pembrolizumab are humanised monoclonal IgG4 antibodies that work on the PD-1 pathway. Despite a growing body of research pertinent to these novel therapies, early indications show that they are limited by their side effect profile. Furthermore, their efficacy appears to be greater in cancers with a high mutational burden. We present two female patients with bilateral reactive dacryoadenitis secondary to ICPi therapy, a finding that to the best of our knowledge was not previously described in the literature. [ABSTRACT FROM AUTHOR]

CD73 is a cell-surface ectoenzyme that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine, which in turn can promote resistance to immune checkpoint blockade therapy. Immune response may therefore be improved by targeting tumor CD73, and this possibility underlines the need to non-invasively assess tumor CD73 level. In this study, we developed a cysteine site-specific 89Zr-labeled anti-CD73 (89Zr-CD73) IgG immuno-PET technique that can image tumor CD73 expression in living bodies. Anti-CD73 IgG was reduced with tris(2-carboxyethyl)phosphine, underwent sulfohydryl moiety–specific conjugation with deferoxamine–maleimide, and was radiolabeled with 89Zr. CT26 mouse colon cancer cells, CT26/CD73 cells engineered to constitutively overexpress CD73, and 4T1.2 mouse breast cancer cells underwent cell binding assays and western blotting. Balb/c nude mice bearing tumors underwent 89Zr-CD73 IgG PET imaging and biodistribution studies. 89Zr-CD73 IgG showed 20-fold higher binding to overexpressing CT26/CD73 cells compared to low-expressing CT26 cells, and moderate expressing 4T1.2 cells showed uptake that was 38.9 ± 1.51% of CT26/CD73 cells. Uptake was dramatically suppressed by excess unlabeled antibody. CD73 content proportionately increased in CT26 and CT26/CD73 cell mixtures was associated with linear increases in 89Zr-CD73 IgG uptake. 89Zr-CD73 IgG PET/CT displayed clear accumulation in CT26/CD73 tumors with greater uptake compared to CT26 tumors (3.13 ± 1.70%ID/g vs. 1.27 ± 0.31%ID/g at 8 days; P = 0.04). Specificity was further supported by low CT26/CD73 tumor-to-blood ratio of 89Zr-isotype-IgG compared to 89Zr-CD73 IgG (0.48 ± 0.08 vs. 2.68 ± 0.52 at 4 days and 0.53 ± 0.07 vs. 4.81 ± 1.02 at 8 days; both P < 0.001). Immunoblotting and immunohistochemistry confirmed strong CD73 expression in CT26/CD73 tumors and low expression in CT26 tumors. 4T1.2 tumor mice also showed clear 89Zr-CD73 IgG accumulation at 8 days (3.75 ± 0.70%ID/g) with high tumor-to-blood ratio compared to 89Zr-isotype-IgG (4.91 ± 1.74 vs. 1.20 ± 0.28; P < 0.005). 89Zr-CD73 IgG specifically targeted CD73 on high expressing cancer cells in vitro and tumors in vivo. Thus, 89Zr-CD73 IgG immuno-PET may be useful for the non-invasive monitoring of CD73 expression in tumors of living subjects. [ABSTRACT FROM AUTHOR]

Background: An increasing number of clinical studies have begun to explore combination strategies with immune checkpoint inhibitors, aiming to present new opportunities for overcoming anti-PD-1 treatment resistance in gastric cancer. Unfortunately, the exploration of certain immune checkpoint inhibitor combination strategies has yielded suboptimal results. Therefore, it is necessary to comprehensively analyze the expression patterns of immune checkpoints and identify optimal combination regimens of anti-PD-1 inhibitors with other immune checkpoint inhibitors. Methods: Leveraging single-cell RNA sequencing (scRNA-seq) and multivariate linear regression interaction models, we dissected the immune checkpoint expression characteristics of CD8+ T cells in gastric cancer and the immune checkpoint expression pattern (ICEP) mediating anti-PD-1 treatment resistance. Furthermore, we employed transcription factor analysis and CellOracle to explore the transcriptional regulatory mechanisms governing CD8+ T cell differentiation fates. Finally, we utilized Nichenet and spatial transcriptomic analysis to investigate the spatial expression patterns of immune checkpoints. Results: Interaction analysis indicated that, among the known immune checkpoints, co-expression of NKG2A and PD-1 might exert a more profound inhibitory effect on the proliferative capacity of CD8+ T cells. The co-expression analysis revealed differential co-expression pattern of PD-1 and NKG2A, defined as ICEP1 (CD8+ T cells co-expressing PD-1, CTLA-4, TIGIT, LAG-3 or CD38) and ICEP2 (CD8+ T cells solely expressing NKG2A or co-expressing with other immune checkpoints), reflecting the co-occurrence pattern of PD-1 and the mutual exclusivity of NKG2A. Further, these two ICEP CD8+ T cell subsets represented distinct CD8+ T cell differentiation fates governed by MSC and RUNX3. Notably, ICEP2 CD8+ T cells were associated with anti-PD-1 therapy resistance in gastric cancer. This phenomenon may be attributed to the recruitment of LGMN+ macrophages mediated by the CXCL16-CXCR6 signaling pathway. Conclusion: This study unveiled two distinct ICEPs and the mutually exclusivity and co-occurrence characteristics of CD8+ T cells in gastric cancer. The ICEP2 CD8+ T cell subset, highly expressed in gastric cancer patients resistant to anti-PD-1 therapy, may be recruited by LGMN+ macrophages through CXCL16-CXCR6 axis. These findings provide evidence for NKG2A as a novel immunotherapeutic target in gastric cancer and offer new insights into combination strategies for immune checkpoint inhibitors in gastric cancer. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumor (IMT) is a rare pathological entity first described in 1939. This lesion is most commonly found in the lungs, but cases involving other systems, such as the central nervous system known as intracranial IMT (IIMT), have also been reported. Diagnosis currently relies on pathological results due to the lack of characteristic imaging changes. Surgical resection is an effective treatment, though the disease is invasive and may recur. Previous literature has reported a high level of programmed death 1 (PD-1) expression in IMT tissues, suggesting that immunotherapy may be effective for this condition. In this case report, we present a middle-aged male who received PD-1 inhibitor and oncolytic adenovirus (Ad-TD-nsIL12) treatment after IIMT resection surgery. This successful approach provides a new direction for the treatment of IIMT. [ABSTRACT FROM AUTHOR]