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Immune checkpoint inhibitors (ICIs) improve outcomes in advanced melanoma, but many patients are refractory or experience relapse. The gut microbiota modulates antitumor responses. However, inconsistent baseline predictors point to heterogeneity in responses and inadequacy of cross-sectional data. We followed patients with unresectable melanoma from baseline and during anti-PD-1 therapy, collecting fecal and blood samples that were surveyed for changes in the gut microbiota and immune markers. Varying patient responses were linked to different gut microbiota dynamics during ICI treatment. We select complete responders by their stable microbiota functions and validate them using multiple external cohorts and experimentally. We identify major histocompatibility complex class I (MHC class I)-restricted peptides derived from flagellin-related genes of Lachnospiraceae (FLach) as structural homologs of tumor-associated antigens, detect FLach -reactive CD8+ T cells in complete responders before ICI therapy, and demonstrate that FLach peptides improve antitumor immunity. These findings highlight the prognostic value of microbial functions and therapeutic potential of tumor-mimicking microbial peptides. [Display omitted] • Microbiome dynamic during immunotherapy correlates with clinical response in melanoma • Stable microbial functions carried by responders hold cross-cohort prognostic value • MHC class I peptides from stable flagellin-related genes mimic tumor-associated antigens • They induce reactivity on PBMC and TIL from responders and improve antitumor immunity Macandog et al. utilized longitudinal data to identify key gut microbial features in immunotherapy-responsive patients with melanoma. Functions stably carried by responders are specific to gut commensals that reportedly evolved mechanisms for human tolerance. These functions could provide advantage during immunotherapy by mimicking tumor antigens that stimulate effective tumor-clearing immunity. [ABSTRACT FROM AUTHOR]

INTRODUCTION: It is unclear how early neuronal deficits occur in tauopathies, if these are associated with changes in neuronal network activity, and if they can be alleviated with therapies. METHODS: To address this, we performed in vivo two‐photon Ca2+ imaging in tauopathy mice at 6 versus 12 months, compared to controls, and treated the younger animals with a tau antibody. RESULTS: Neuronal function was impaired at 6 months but did not deteriorate further at 12 months, presumably because cortical tau burden was comparable at these ages. At 6 months, neurons were mostly hypoactive, with enhanced neuronal synchrony, and had dysregulated responses to stimulus. Ex vivo, electrophysiology revealed altered synaptic transmission and enhanced excitability of motor cortical neurons, which likely explains the altered network activity. Acute tau antibody treatment reduced pathological tau and gliosis and partially restored neuronal function. DISCUSSION: Tauopathies are associated with early neuronal deficits that can be attenuated with tau antibody therapy. Highlights: Neuronal hypofunction in awake and behaving mice in early stages of tauopathy.Altered network activity disrupted local circuitry engagement in tauopathy mice.Enhanced neuronal excitability and altered synaptic transmission in tauopathy mice.Tau antibody acutely reduced soluble phospho‐tau and improved neuronal function. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM), a prevalent and aggressive brain tumor, poses significant treatment challenges due to its rapid progression and the difficulty in achieving complete surgical resection. The current treatment regime, primarily surgery followed by radiotherapy and chemotherapy, offers limited success, with a five-year survival rate of less than 10 %. For addressing the challenges faced in the treatment of GBM, an approach using a biopolymer implant constructed with dynamic reversible covalent bonds, was designed to achieve controlled and constant-rate release of chemotherapy drug (Temozolomide, TMZ), immune adjuvant (Resiquimod, R848) and checkpoint inhibitor (5-carboxy-8-hydroxyquinoline, IOX1). The safety evaluation demonstrated the biocompatibility of the implants, with no significant inflammatory response or adverse effects on various systemic organs. In vivo antitumor study showed that the local delivery of drug combination via this implant significantly inhibited tumor recurrence of orthotopic GBM. Immune analysis revealed that the combination of the three drugs effectively activated systemic antitumor immune responses and induced memory effects. The synergistic mechanism of the drug combination was further validated by RNA whole sequencing. The innovative approach of combining chemotherapy and immunotherapy in biopolymer immune implants for GBM treatment showed promising and opens new avenues for treating GBM, particularly in addressing postoperative recurrence. Our research introduces a pioneering approach in treating orthotopic brain glioblastoma (GBM), characterized by inevitable tumor recurrence, poor immune infiltration and the restrictive nature of the blood-brain barrier. To break the impasse of ineffective treatment for GBM, the innovative use of dynamically reversible covalent bonds in polymer matrix ensures the controlled, stable and sustained release of drug combinations of the chemotherapeutic agent temozolomide, immune adjuvants and checkpoint inhibitors, which maintains the optimal concentration in the tumor, overcoming problems associated with conventional chemotherapy such as systemic toxicity and low tumor targeting. Empirical evidence from in vivo experiments on the rat GBM model demonstrates significant outcomes: 90 % tumor size reduction and prolonged survival with over 70 % tumor cure rate. [Display omitted] [ABSTRACT FROM AUTHOR]

The treatment of melanoma has witnessed groundbreaking changes over the last decade, transforming the standard of care for patients with high-risk, advanced or metastatic disease. Whilst the treatment approach depends on the stage of disease, the management of primary melanoma remains complete wide excision of the primary. Sentinel node biopsy is offered in selected higher risk melanoma and complete nodal dissection is performed in patients who present with palpable nodal disease. Tumour genetic analysis for BRAF mutation should be performed in all patients with stage IIB to IV disease as this will determine if patients are suitable for targeted treatment with BRAF and MEK inhibitors. Systemic treatment with targeted treatment with BRAF and MEK inhibitors and immunotherapy are recommended as adjuvant treatment options and in metastatic settings. Patients with a personal or family history of three or more melanomas require genetic assessment. [ABSTRACT FROM AUTHOR]

• Rasmussen syndrome (RS) currently lacks detailed diagnostic/treatment algorithms. • The survey highlights trends and significant variations in RS management. • Variations in practice are targets for research and consensus guidelines in RS. Rasmussen syndrome (RS) is marked by progressive unihemispheric atrophy, resulting in hemiparesis, refractory epilepsy, and cognitive/language decline. Detailed diagnostic and treatment algorithms are currently lacking. We aimed to survey medical providers on their current practices in the diagnosis and treatment of RS. A steering committee was formed to create the survey, which was disseminated to the international medical community. One hundred twelve surveys were completed. Descriptive statistics, as well as comparisons by level of experience, patient age group cared for, and geographic region using Fisher's exact test, were conducted. Analysis of cerebrospinal fluid (82 %) and serum (78 %) for autoimmune encephalitis (AE) are completed by most, while approximately one-third obtain genetic and metabolic studies in all patients (36 % and 38 %, respectively). Providers in US and Europe more readily pursue serum AE antibody panels (85 % and 85 %, respectively, versus 67 %, p = 0.019) and genetic testing (56 % and 47 %, respectively, versus 14 %, p < 0.001) than the rest of the world. Thirty-six percent proceed to biopsy in patients otherwise meeting diagnostic criteria, and US providers are more likely to suggest this than others (73 % versus 14–41 %, p < 0.001). Opinions differed on the prioritization of hemispherectomy/hemispherotomy versus immunotherapy in 14 clinical scenarios with various neurologic deficit severity provided. Preferred immunotherapy regimens also varied, with US providers more often choosing IVIG as first-line (67 %) compared to others (28 %-32 %, p = 0.030). Surgical standard of care was identified as functional hemispherectomy or hemispherotomy by 90 %. The survey highlights trends but also significant variations in clinical practice that can serve as targets for future research and expert consensus guidelines. [ABSTRACT FROM AUTHOR]

For almost a decade predicting the response of malignant tumours to treatment with immunotherapies has been dependent on PD-L1 expression by immunohistochemistry. Much has been learned about the uniquely challenging application of PD-L1 immunohistochemistry which is utilized in a constantly expanding array of tumour types and clinical contexts. More recently, other predictive biomarkers have acquired clinical validation including tumour mismatch repair deficiency. In this short review, I will assess the strengths and weaknesses of PD-L1 immunohistochemistry, including pre-analytics, analytics and post-analytics in the context of the complex underlying biology. In doing so, I hope to provide some practical guidance that will help optimize its application in routine practice. I will also highlight the various contexts in which immunohistochemistry for PD-L1 and mis-match repair is used to predict response to immunotherapies and how ongoing developments of novel immunohistochemistry based biomarkers might assist in strengthening the ability to predict response to immunotherapies. [ABSTRACT FROM AUTHOR]

Immunotherapies have revolutionized the management of advanced cutaneous malignancies. However, some patients fail to respond to these therapies, others are ineligible because of comorbidities, and a minority of patients experience treatment-limiting systemic immune-related adverse events. To address these issues and expand treatment options for patients with early-stage disease, a variety of immunotherapies are being developed for direct intratumoral administration. Agents including oncolytic viruses, monoclonal antibodies, cytokines, peptides, and pattern-recognition receptor agonists have been engineered to evoke a local immune response while minimizing systemic toxicity and have shown favorable results in preclinical and early clinical testing. This review covers the current landscape of intratumoral immunotherapies for the treatment of cutaneous melanoma, squamous cell carcinoma, and basal cell carcinoma, highlighting the diverse array of agents being explored and their potential benefits and challenges. [ABSTRACT FROM AUTHOR]

MYC has been implicated in the pathogenesis of a wide range of human tumors and has been described for many years as a transcription factor that regulates genes with pleiotropic functions to promote tumorigenic growth. However, despite extensive efforts to identify specific target genes of MYC that alone could be responsible for promoting tumorigenesis, the field is yet to reach a consensus whether this is the crucial function of MYC. Recent work shifts the view on MYC's function from being a gene‐specific transcription factor to an essential stress resilience factor. In highly proliferating cells, MYC preserves cell integrity by promoting DNA repair at core promoters, protecting stalled replication forks, and/or preventing transcription‐replication conflicts. Furthermore, an increasing body of evidence demonstrates that MYC not only promotes tumorigenesis by driving cell‐autonomous growth, but also enables tumors to evade the host's immune system. In this review, we summarize our current understanding of how MYC impairs antitumor immunity and why this function is evolutionarily hard‐wired to the biology of the MYC protein family. We show why the cell‐autonomous and immune evasive functions of MYC are mutually dependent and discuss ways to target MYC proteins in cancer therapy. [ABSTRACT FROM AUTHOR]

Immunotherapy has achieved tremendous success in melanoma. However, only around 50% of advanced melanoma patients benefit from immunotherapy. Cyclin‐dependent kinase inhibitor 2A (CDKN2A), encoding the two tumor‐suppressor proteins p14ARF and p16INK4a, belongs to the most frequently inactivated gene loci in melanoma and leads to decreased T cell infiltration. While the role of p16INK4a has been extensively investigated, knowledge about p14ARF in melanoma is scarce. In this study, we elucidate the impact of reduced p14ARF expression on melanoma immunogenicity. Knockdown of p14ARF in melanoma cell lines diminished their recognition and killing by melanoma differentiation antigen (MDA)‐specific T cells. Resistance was caused by a reduction of the peptide surface density of presented MDAs. Immunopeptidomic analyses revealed that antigen presentation via human leukocyte antigen class I (HLA‐I) molecules was enhanced upon p14ARF downregulation in general, but absolute and relative expression of cognate peptides was decreased. However, this phenotype is associated with a favorable outcome for melanoma patients. Limiting Wnt5a signaling reverted this phenotype, suggesting an involvement of non‐canonical Wnt signaling. Taken together, our data indicate a new mechanism limiting MDA‐specific T cell responses by decreasing both absolute and relative MDA‐peptide presentation in melanoma. [ABSTRACT FROM AUTHOR]

The regulation of intracellular ionic homeostasis to trigger antigen-specific immune responses has attracted extensive interest in tumor therapy. In this study, we developed a dual-pathway nanoreactor, Au-Cu 2-x Se@ZIF-8@P18 NPs (ACS-Z-P NPs), which targets danger-associated molecular patterns (DAMPs) and releases Zn2+ and reactive oxygen species (ROS) within the tumor microenvironment (TME). Zn2+ released from the metal–organic frameworks (MOFs) was deposited in the cytoplasm, leading to aberrant transcription levels of intracellular zinc-regulated proteins and DNA damage, thereby inducing pyroptosis and immunogenic cell death (ICD) dependent on caspase1/gasdermin D (GSDMD) pathway. Furthermore, upon laser irradiation, ACS-Z-P NPs could break through the limitations of inherent defects of immunosuppression in TME, enhance ROS generation through a Fenton-like reaction cascade, which subsequently triggered the activation of inflammatory vesicles and the release of damage-associated molecular patterns (DAMPs). This cascade effect led to the amplification of pyroptosis and immunogenic cell death (ICD), thereby remodeling the immunosuppressed TME. Consequently, this process improved dendritic cell (DC) antigen presentation and augmented anti-tumor T-cell responses, effectively initiating antigen-specific immune responses and further enhancing pyroptosis and ICD. This study explores the therapeutic properties of these mechanisms in detail. The synthesized Au-Cu 2-x Se@ZIF-8@P18 nanoparticles (ACS-Z-Ps) can effectively enhance the bodyʼs immune response by regulating zinc ion levels within cells. This regulation leads to abnormal levels of zinc-regulated protein transcription and DNA damage, which induces cellular pyroptosis. As a result, antigen presentation to dendritic cells (DCs) is improved, and anti-tumor T-cell responses are enhanced. The ACS-Z-P NPs overcome the limitations of ROS deficiency and immunosuppression in the tumor microenvironment by using H 2 O 2 in the tumor microenvironment through a Fenton-like reaction. This leads to an increased production of ROS and O 2 , remodeling of the immunosuppressed tumor microenvironment, and enhanced induction of cell pyroptosis and immunogenic cell death. ACS-Z-P NPs targeted B16 cells using the photosensitizer P18 in combination with PDT treatment. This approach significantly inhibited the proliferation of B16 cells and effectively inhibited tumor growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Protein kinase C α (PKC α) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKC α inhibition enhances CD8+ T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKC α as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKC α -mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKC α inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo. Clinical analysis revealed that PKC α expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKC α , identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKC α in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC. PKC α inhibitors enhance tumor evasion by maintaining PD-L1 stability, which impairs their tumor-inhibiting effect. The PD-1/PD-L1 blockade therapies synergistically enhance the anti-tumor efficacy of PKC α inhibitors in breast cancer. [Display omitted] [ABSTRACT FROM AUTHOR]

Cell death is a central process for organismal health. Pyroptosis, namely pyroptotic cell death, is recognized as a critical type that disrupts membrane and triggers pro-inflammatory cytokine secretion via gasdermins, providing a robust form of cytolysis. Meanwhile, along with the thorough research, a great deal of evidence has demonstrated the dual effects of pyroptosis in host defense and inflammatory diseases. More importantly, the recent identification of abundant gasdermin-like proteins in bacteria and fungi suggests an ancient origin of pyroptosis-based regulated cell death in the life evolution. In this review, we bring a general overview of pyroptosis pathways focusing on gasdermin structural biology, regulatory mechanisms, and recent progress in induction and inhibition strategies for disease treatment. We look forward to providing an insightful perspective for readers to comprehend the frame and challenges of the pyroptosis field, and to accelerating its clinical application. This review brings a general overview of pyroptosis pathway focusing on gasdermin structural biology, regulatory mechanisms, and intervention strategies for immunotherapy of diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Toll-like receptor (TLR) agonists, as promising adjuvants and immunotherapeutic agents, have the potential to enhance immune responses and modulate antigen-dependent T-cell immune memory through activation of distinct signaling pathways. However, their clinical application is hindered by uncontrolled systemic inflammatory reactions. Therefore, it is imperative to create a vaccine adjuvant for TLR receptors that ensures both safety and efficacy. In this study, we designed lymph node-targeted cholesterolized TLR7 agonist cationic liposomes (1V209-Cho-Lip+) to mitigate undesired side effects. Co-delivery of the model antigen OVA and cholesterolized TLR7 agonist facilitated DC maturation through TLR activation while ensuring optimal presentation of the antigen to CD8+ T cells. The main aim of the present study is to evaluate the adjuvant effectiveness of 1V209-Cho-Lip+ in tumor vaccines. Following immunization with 1V209-Cho-Lip++OVA, we observed a pronounced "depot effect" and enhanced trafficking to secondary lymphoid organs. Prophylactic vaccination with 1V209-Cho-Lip++OVA significantly delays tumor development, prolongs mouse survival, and establishes durable immunity against tumor recurrence. Additionally, 1V209-Cho-Lip++OVA, while used therapeutic tumor vaccine, has demonstrated its efficacy in inhibiting tumor progression, and when combined with anti-PD-1, it further enhances antitumor effects. Therefore, the co-delivery of antigen and lymph node-targeted cholesterolized TLR7 agonist shows great promise as a cancer vaccine. 1V209-Cho-Lip++OVA effectively co-delivers antigen and TLR7 agonist, thereby augmenting both humoral and cellular immunity to exert a superior anti-tumor effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Uterine cancer is a prevalent gynecological malignancy globally. Endometrial carcinosarcomas constitute a rare and aggressive subtype of uterine malignancy. In recent years, immunotherapy has emerged as a treatment option after the failure of platinum-based chemotherapy. This case series explores the use of pembrolizumab and lenvatinib in treating endometrial carcinosarcoma. This retrospective case series was conducted at a single tertiary care center in northern New Jersey, United States, and included patients seen between 2019 and 2023 who had confirmed uterine carcinosarcoma treated with pembrolizumab and lenavatinib. Patient demographics, oncologic characteristics, and details of immunotherapy were extracted from electronic medical records (Epic). Statistical analysis included survival analysis for progressionfree survival (PFS) and overall survival (OS). A total of eight patients with endometrial carcinosarcoma, microsatellite stable, were treated with pembrolizumab plus lenvatinib and included in the case series. All patients received cytoreductive surgery and chemotherapy with carboplatin plus paclitaxel. The median follow-up duration with the oncologist was 5.6 months (IQR (Interquartile range): 3.5, 9.0). OS ranged from 0.4 to 19.3 months. One patient was excluded from the OS analysis due to a loss of follow-up. The median PFS was 3.6 months (IQR: 1.8, 4.4). This case series provides valuable insight into applying pembrolizumab and lenvatinib as a second-line treatment for endometrial carcinosarcoma after the failure of platinum-based chemotherapy. The observed improvements in PFS and OS, coupled with manageable side effects, highlight the potential efficacy of this treatment. [ABSTRACT FROM AUTHOR]

Gliomas are the most prevalent primary malignant brain tumors worldwide, with glioblastoma (GBM) being the most common and aggressive type. The standard therapy for GBM has remained unchanged for nearly two decades, with no significant improvement in survival outcomes. Despite several barriers such as the tumor microenvironment (TME) and blood–brain barrier, immunotherapies bring new hope for the treatment of GBM. To better understand the development and progress of immunotherapies in GBM, we made this scientometric analysis of this field. A total of 3753 documents were obtained from the Web of Science Core Collection, with publication years ranging from 1999 to 2022. The Web of Science platform, CiteSpace, and VOS viewer were used to conduct the scientometric analysis. The results of scientometric analysis showed that this field has recently become a popular topic of interest. The United States had the most publications among 89 countries or regions. Keyword analysis indicated significant areas in the field of immunotherapies for GBM, especially TME, immune checkpoint blockades (ICBs), chimeric antigen receptor T (CAR-T) cells, vaccines, and oncolytic viruses (OVs). Overall, we hope that this scientometric analysis can provide insights for researchers and promote the development of this field. • This is the first scientometric analysis of immunotherapies for gliomas. • The research situations, hotspots, and trends of this field are obtained based on the scientometric analysis. • The significance of ICB, CAR-T cell therapy, vaccine therapy, OV therapy, as well as the TME in GBM is stressed. • The timeline of landmark achievements in immunotherapies for GBM is made. [ABSTRACT FROM AUTHOR]

The advent of liquid biopsies has brought significant changes to the diagnosis and monitoring of non-small cell lung cancer (NSCLC), presenting both promise and challenges. Molecularly targeted drugs, capable of enhancing survival rates, are now available to around a quarter of NSCLC patients. However, to ensure their effectiveness, precision diagnosis is essential. Circulating tumor DNA (ctDNA) analysis as the most advanced liquid biopsy modality to date offers a non-invasive method for tracking genomic changes in NSCLC. The potential of ctDNA is particularly rooted in its ability to furnish comprehensive (epi-)genetic insights into the tumor, thereby aiding personalized treatment strategies. One of the key advantages of ctDNA-based liquid biopsies in NSCLC is their ability to capture tumor heterogeneity. This capability ensures a more precise depiction of the tumor's (epi-)genomic landscape compared to conventional tissue biopsies. Consequently, it facilitates the identification of (epi-)genetic alterations, enabling informed treatment decisions, disease progression monitoring, and early detection of resistance-causing mutations for timely therapeutic interventions. Here we review the current state-of-the-art in ctDNA-based liquid biopsy technologies for NSCLC, exploring their potential to revolutionize clinical practice. Key advancements in ctDNA detection methods, including PCR-based assays, next-generation sequencing (NGS), and digital PCR (dPCR), are discussed, along with their respective strengths and limitations. Additionally, the clinical utility of ctDNA analysis in guiding treatment decisions, monitoring treatment response, detecting minimal residual disease, and identifying emerging resistance mechanisms is examined. Liquid biopsy analysis bears the potential of transforming NSCLC management by enabling non-invasive monitoring of Minimal Residual Disease and providing early indicators for response to targeted treatments including immunotherapy. Furthermore, considerations regarding sample collection, processing, and data interpretation are highlighted as crucial factors influencing the reliability and reproducibility of ctDNA-based assays. Addressing these challenges will be essential for the widespread adoption of ctDNA-based liquid biopsies in routine clinical practice, ultimately paving the way toward personalized medicine and improved outcomes for patients with NSCLC. [ABSTRACT FROM AUTHOR]

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer. [ABSTRACT FROM AUTHOR]

Immunotherapy, as a promising treatment strategy for cancer, has been widely employed in clinics, while its efficiency is limited by the immunosuppression of tumor microenvironment (TME). Tumor-associate macrophages (TAMs) are the most abundant immune cells infiltrating the TME and play a crucial role in immune regulation. Herein, a M0-type macrophage-mediated drug delivery system (PR-M) was designed for carrying Toll-like receptors (TLRs) agonist-loaded nanoparticles. When TLR agonist R848 was released by responding to the TME, the PR-Ms were polarized from M0-type to M1-type and TAMs were also stimulated from M2-type to M1-type, which eventually reversed the immunosuppressive states of TME. By synergizing with the released R848 agonists, the PR-M significantly activated CD4+ and CD8+ T cells in the TME and turned the 'cold' tumor into 'hot' tumor by regulating the secretion of cytokines including IFN-γ, TNF-α, IL-10, and IL-12, thus ultimately promoting the activation of antitumor immunity. In a colorectal cancer mouse model, the PR-M treatment effectively accumulated at the tumor site, with a 5.47-fold increase in M1-type and a 65.08 % decrease in M2-type, resulting in an 85.25 % inhibition of tumor growth and a 87.55 % reduction of tumor volume compared with the non-treatment group. Our work suggests that immune cell-mediated drug delivery systems can effectively increase drug accumulation at the tumor site and reduce toxic side effects, resulting in a strong immune system for tumor immunotherapy. The formation of TME and the activation of TAMs create an immunosuppressive network that allows tumor to escape the immune system and promotes its growth and spread. In this study, we designed an M0-type macrophage-mediated drug delivery system (PR-M). It leverages the synergistic effect of macrophages and agonists to improve the tumor immunosuppressive micro-environment by increasing M1-type macrophages and decreasing M2-type macrophages. As part of the treatment, the drug-loaded macrophages endowed the system with excellent tumor targeting. Furthermore, loading R848 into TME-responsive nanoparticles could protect macrophages and reduce the potential toxicity of agonists. Further investigations demonstrated that the designed PR-M could be a feasible strategy with high efficacy in tumor targeting, drug loading, autoimmunity activation, and lower side effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadliest cancers worldwide. While the use of targeted therapies and immunotherapies in precision medicine has improved outcomes for some patients, a significant portion of individuals still fail to benefit, emphasizing the need to investigate the underlying mechanisms of resistance. Survival analyses have shown that NSCLC patients with SMARCA4 mutations often have poor prognoses. SMARCA4, the core ATPase subunit of the SWI/SNF chromatin remodeling complex, plays a critical role in regulating gene transcription by modifying chromatin accessibility. This influences essential cellular processes such as differentiation and cell cycle regulation, and SMARCA4 is widely regarded as a tumor suppressor. This review will explore the role of SMARCA4 mutations in tumor progression, its clinicopathological features in NSCLC, its impact on treatment outcomes, and potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background and objective The malignant tumor that has the highest global morbidity and death rate is lung cancer, which primarily affects the elderly. The therapy landscape for non-small cell lung cancer (NSCLC) has transformed with the introduction of immune checkpoint inhibitors (ICIs). The purpose of this study was to compare the safety and efficacy of immune monotherapy and immunotheray combined with chemotherapy in patients with advanced NSCLC aged 75 years and above. Methods This study retrospectively analyzed 111 patients with advanced NSCLC who were at least 75 years old and received treatment at the First or Fifth Medical Centers of the People's Liberation Army General Hospital from January 2018 to October 2022. These patients underwent first-line or second-line treatment, with 70 receiving immunotherapy combined with chemotherapy and 41 receiving immunotherapy alone. Propensity score matching (PSM) was used to match the baseline characteristics of the patients, including age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, and the number of treatment lines. The study endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Results The median OS for the immunotherapy combined with chemotherapy group was 27.87 months, and the median PFS was 11.50 months. The median OS for the immune monotherapy group was 34.93 months, and the median PFS was 17.00 months. There were no significant differences in OS (P=0.722) and PFS (P=0.474) between the two groups, but a significant difference was observed in ORR (P=0.025). After PSM matching, each group comprised 27 patients. The median OS for the immunotherapy combined with chemotherapy group was 17.70 months, the median PFS was 8.97 months. The median OS for the immune monotherapy group was 17.87 months, and the median PFS was 11.53 months. No significant differences were observed in OS (P=0.635), PFS (P=0.878) and ORR (P=0.097). In terms of safety, the overall incidence of adverse events (AEs) before matching was 62.86% in the immunotherapy combined with chemotherapy group, which was higher than 41.46% in the immune monotherapy group (P=0.029), while there was no difference in the incidence of AEs of grade 3 or above between the two groups (P=0.221). After matching, AEs occurred in 17 (62.96%) patients in the immunotherapy combined with chemotherapy group and 13 (48.15%) in the immune monotherapy group. There were no significant differences in the overall incidence of AEs (P=0.273) or the incidence of grade 3 or above (P=0.299) between the two groups. Conclusion Immunotherapy combined with chemotherapy does not significantly improve OS or PFS in patients with NSCLC aged 75 years and above when compared to immunotherapy alone, and this conclusion was further validated by the analysis after PSM. The safety assessment suggests that before matching, the incidence of AEs of any grade in the immunotherapy combined with chemotherapy group was higher. Still, the two groups had no difference in the incidence of AEs of grade 3 or above. Following matching, the tolerability of the treatment was similar in both groups. According to the safety assessment, the unique circumstances and course of treatment for geriatric patients with advanced NSCLC should be considered. [ABSTRACT FROM AUTHOR]

Background: Sinonasal tumors represent a rare and heterogeneous group of rhinologic neoplasms. Even with advancements in surgical approaches, mortality rates of patients with sinonasal adenocarcinoma (SNAC) have not significantly improved and persistently high rates of recurrence in certain patients with inverted papilloma (IP) are seen. The use of 5-fluorouracil (5-FU) has been successfully described as an adjuvant treatment of SNAC and in the prevention of IP recurrence. Objective: This review aims to present the current evidence on the management of SNAC and IP with topical 5-FU. Methods: A three-author independent literature review was conducted to identify research involving the use of topical 5-FU for the treatment of SNAC and IP. A total of nine papers on the treatment of SNAC and IP were collected. Results: The earliest study looking at the combination of adjuvant low-dose radiation and topical 5-FU for adenocarcinoma of the ethmoid sinus showed a 5-year survival rate of 100%. A follow-up study evaluating a similar protocol reported adjusted disease-free survival at 2, 5, and 10 years of 96%, 87%, and 74%, respectively. Similar results have been demonstrated for adjuvant 5-FU use following endoscopic resection and have even been described in the novel setting of transcutaneous 5-FU delivery following frontal trephination. Topical 5-FU has also been described in the treatment of aggressive IP. The largest case series described the use of 5-FU for eighteen cases and demonstrated only a single recurrence. Conclusion: The use of topical 5-FU currently represents an underutilized therapeutic modality within the treatment of rhinologic neoplasms. Available literature suggests that neoadjuvant use of topical 5-FU can improve survival and decrease recurrence for SNAC and IP. However, the small sample sizes prevent advocation for routine use in the general population and further research on 5-FU is necessary. [ABSTRACT FROM AUTHOR]

Background/Purpose: Bilateral diffuse uveal melanocytic proliferation is a paraneoplastic syndrome affecting the eye that is a sign of poor prognosis of underlying malignancy. This is the first documented case to show serial and sustained improvement of bilateral diffuse uveal melanocytic proliferation after immunotherapy in the setting of primary non-small-cell carcinoma of the lung. Methods: Single-center, case report. Results: A 65-year-old man reported a gradual decrease in vision and floaters in the right eye after cataract surgery. Fundus examination demonstrated diffuse multiple brown subretinal lesions bilaterally. Next-generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1c.411A. T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Plasma samples from the patient and a control patient with no history of cancer and/or paraneoplastic syndrome were cultured with neonatal melanocytes, which revealed a .180% increase in proliferation of normal neonatal melanocytes compared with the control. Pembrolizumab therapy was initiated, which resulted in shrinkage and stabilization of the lesions documented in serial diagnostic testing. Conclusion: In conclusion, we report a cytologically and serologically confirmed case of bilateral diffuse uveal melanocytic proliferation in a patient with a primary non-small-cell carcinoma of the lung. Next-generation sequencing of melanocytic tissue of the patient described in this case revealed a specific RB1 c.411A. T (p.Glu137Asp) variant with an allele frequency of 44.8%, consistent with heterozygosity. Furthermore, we show documented serial improvement in the patient's ocular and systemic disease with treatment. This case as one of the longest surviving confirmed cases of a patient with bilateral diffuse uveal melanocytic proliferation. [ABSTRACT FROM AUTHOR]

Immunotherapy is an important cancer treatment method that offers hope for curing cancer patients. While immunotherapy has achieved initial success, a major obstacle to its widespread adoption is the inability to benefit the majority of patients. The success or failure of immunotherapy is closely linked to the tumor's immune microenvironment. Recently, there has been significant attention on strategies to regulate the tumor immune microenvironment in order to stimulate anti-tumor immune responses in cancer immunotherapy. The distinctive physical properties and design flexibility of nanomedicines have been extensively utilized to target immune cells (including tumor-associated macrophages (TAMs), T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated fibroblasts (TAFs)), offering promising advancements in cancer immunotherapy. In this article, we have reviewed treatment strategies aimed at targeting various immune cells to regulate the tumor immune microenvironment. The focus is on cancer immunotherapy models that are based on nanomedicines, with the goal of inducing or enhancing anti-tumor immune responses to improve immunotherapy. It is worth noting that combining cancer immunotherapy with other treatments, such as chemotherapy, radiotherapy, and photodynamic therapy, can maximize the therapeutic effects. Finally, we have identified the challenges that nanotechnology-mediated immunotherapy needs to overcome in order to design more effective nanosystems. Nanomedicine activates anti-tumor immunity by regulating immune cells, thereby remodeling the immunosuppressive microenvironment and enhancing anti-tumor efficiency. [Display omitted] [ABSTRACT FROM AUTHOR]

The immunosuppressive phenotype of tumor cells extensively attenuates the immune activation effects of traditional treatments. In this work, a transferrin receptor (TfR) targeted immunostimulant (PTI) is fabricated for photodynamic immunotherapy against metastatic tumors by interrupting β -catenin signal pathway. To synthesize PTI, the photosensitizer conjugated TfR targeting peptide moiety (Palmitic-K(PpIX)-HAIYPRH) is unitized to encapsulate the transcription interrupter of ICG-001. On the one hand, the recognition of PTI and TfR can promote drug delivery into tumor cells to destruct primary tumors through photodynamic therapy and initiate an immunogenic cell death with the release of tumor-associated antigens. On the other hand, PTI will interrupt the binding between β -catenin and cAMP response element-binding protein (CREB), regulating the gene transcription to downregulate programmed death ligand 1 (PD-L1) while upregulating C–C motif chemokine ligand 4 (CCL4). Furthermore, the elevated CCL4 can recruit the dendritic cells to present tumor-specific antigens and promote T cells activation and infiltration, and the downregulated PD-L1 can avoid the immune evasion of tumor cells and activate systemic anti-tumor immunity to eradicate lung metastasis. This work may inspire the development of antibody antibody-free strategy to activate systemic immune response in consideration of immunosuppressive conditions. A transferrin receptor-targeted immunostimulant (PTI) is developed for photodynamic immunotherapy against metastatic tumors by downregulating programmed death ligand 1 (PD-L1) and upregulating C–C motif chemokine ligand 4 (CCL4). [Display omitted] [ABSTRACT FROM AUTHOR]

Ferroptosis is a recently discovered pathway for regulated cell death pathway. However, its efficacy is affected by limited iron content and intracellular ion homeostasis. Here, we designed a metal-organic framework (MOF)-based nanoplatform that incorporates calcium peroxide (CaO 2) and oridonin (ORI). This platform can improve the tumor microenvironment and disrupt intracellular iron homeostasis, thereby enhancing ferroptosis therapy. Fused cell membranes (FM) were used to modify nanoparticles (ORI@CaO 2 @Fe-TCPP, NPs) to produce FM@ORI@CaO 2 @Fe-TCPP (FM@NPs). The encapsulated ORI inhibited the HSPB1/PCBP1/IREB2 and FSP1/COQ10 pathways simultaneously, working in tandem with Fe3+ to induce ferroptosis. Photodynamic therapy (PDT) guided by porphyrin (TCPP) significantly enhanced ferroptosis through excessive accumulation of reactive oxygen species (ROS). This self-amplifying strategy promoted robust ferroptosis, which could work synergistically with FM-mediated immunotherapy. In vivo experiments showed that FM@NPs inhibited 91.57% of melanoma cells within six days, a rate 5.6 times higher than chemotherapy alone. FM@NPs were biodegraded and directly eliminated in the urine or faeces without substantial toxicity. Thus, this study demonstrated that combining immunotherapy with efficient ferroptosis induction through nanotechnology is a feasible and promising strategy for melanoma treatment. An iron-based metal-organic framework nanoplatform for enhanced ferroptosis therapy as a comprehensive antitumor strategy was reported. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent advances in immunotherapy using immune checkpoint inhibitors (ICIs) for various cancers have also highlighted a rise in immune-related adverse events, including hepatitis, potentially leading to the discontinuation of treatment. This study aimed to evaluate the prevalence of hepatitis in metastatic colorectal cancer (mCRC) patients undergoing different ICI therapies. An extensive search of PubMed, PubMed Central, and Google Scholar up to November 2023 identified relevant studies. After excluding non-English articles, case reports, reviews, ongoing trials, and studies combining other therapies, five studies qualified for inclusion. Data extraction and statistical analyses were performed using Excel and Comprehensive Meta-Analysis software, respectively. Results from a subgroup analysis indicated that the incidence of hepatitis was comparable among patients treated with PD-1 monotherapy, PDL-1 monotherapy, and combination PD-1 and CTLA-4 therapy, with rates of 2.6%, 2.2%, and 1.7% for any grade and 2.1%, 2.2%, and 1.7% for grade ≥3 hepatitis, respectively. Naive-treated mCRC patients exhibited higher hepatitis rates than those previously treated (3.2% vs 1.6% and 2.6% vs 1.6% for any grade and grade ≥3, respectively). This study underscores the similar risk of hepatitis across different ICI therapies, with an increased incidence in naive-treated mCRC patients. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a major health problem. It is one of the most common types of stroke and results in mortality in approximately half of patients. More than half of the fatalities occur in the first 2 days. In addition to the mass effect after ICH hemorrhage, complex pathophysiological mechanisms such as intracranial vessel vasospasm, microthrombosis, and inflammatory immune reaction also increase brain damage. Both resident (including microglia and astrocytes) and circulating immune cells (including neutrophils, macrophages, and lymphocytes) involved in the inflammatory process. The inflammatory response is especially harmful in the acute phase due to harmful substances secreted by infiltrating immune cells. The inflammatory response also has beneficial effects, especially in the later stages. Their role in pathophysiology makes immune cells important therapeutic targets. General immunosuppressive approaches and depleting cell groups such as neutrophils or keeping them away from the lesion site may not be sufficient to prevent poor outcomes after ICH. This is most likely because they suppress anti-inflammatory activities and pro-inflammatory effects. Instead, directing immune cells to the beneficial subpopulation seems like a more rational solution. The pro-inflammatory N1 subpopulation of neutrophils damages the tissue surrounding ICH. In contrast, the N2 subpopulation is associated with anti-inflammatory reactions and tissue repair. Studies show that when neutrophils are polarized toward the N2 subpopulation, clinical outcomes improve and the volume of the infarct decreases. However, more research is still needed. This study aims to evaluate the role of neutrophils as immunotherapeutic targets in ICH in light of current knowledge. [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]

Copyright of Arquivos Brasileiros de Oftalmologia is the property of Arquivos Brasileiros de Oftalmologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Most patients receiving atezolizumab-bevacizumab (AB) for hepatocellular carcinoma will eventually experience disease progression. Randomized clinical trials (RCTs) are undergoing to identify second-line treatments. Where RCTs are unavailable or patients are non-eligible, sorafenib is often prescribed based on approval and reimbursement policies. However, evidence supporting this approach is minimal. To assess the efficacy and safety of sorafenib in patients who permanently discontinued AB. The ARTE database prospectively collects patients treated with AB in a real-life setting. We analysed the outcome of patients who received sorafenib as second-line treatment. Amongst 213 patients, 130 (61.0 %) permanently discontinued AB. Of them, 54 received second- line treatments, and sorafenib was prescribed in 40 patients. The disease control rate (DCR) was 10.0 %. The median progression-free (PFS) and overall survival were 3.3 (95 % confidence interval [CI] 2.7-3.9) and 6.9 months (95 % CI 2.7-11.1), respectively. In patients progressing under AB, the efficacy of sorafenib on different outcomes is limited. [ABSTRACT FROM AUTHOR]

Cancer has agonized the human race for millions of years. The present decade witnesses biological therapeutics to combat cancer effectively. Cancer Immunotherapy involves the use of therapeutics for manipulation of the immune system by immune agents like cytokines, vaccines, and transfection agents. Recently, this therapeutic approach has got vast attention due to the current pandemic COVID-19 and has been very effective. Concerning cancer, immunotherapy is based on the activation of the host's antitumor response by enhancing effector cell number and the production of soluble mediators, thereby reducing the host's suppressor mechanisms by induction of a tumour killing environment and by modulating immune checkpoints. In the present era, immunotherapies have gained traction and momentum as a pedestal of cancer treatment, improving the prognosis of many patients with a wide variety of haematological and solid malignancies. Food supplements, natural immunomodulatory drugs, and phytochemicals, with recent developments, have shown positive trends in cancer treatment by improving the immune system. The current review presents the systematic studies on major immunotherapeutics and their development for the effective treatment of cancers as well as in COVID-19. The focus of the review is to highlight comparative analytics of existing and novel immunotherapies in cancers, concerning immunomodulatory drugs and natural immunosuppressants, including immunotherapy in COVID-19 patients. [ABSTRACT FROM AUTHOR]

Immune check inhibitors (ICIs) are a class of biologic therapy used for cancer treatment that enhances T-cell recognition of cancer cells. Toxicities from ICIs are described as immune-related adverse events (irAEs) with Grade 1 to 2 irAEs representing mild-to-moderate toxicity and Grade 3 to 4 irAEs representing severe to life-threatening toxicity. The long half-life of ICIs contributes to the extended and unpredictable nature of irAEs. ICI therapy is typically stopped for Grade 3 to 4 irAEs except for endocrinopathies if clinically optimized. Toxicities can involve any organ system; therefore, a thorough preoperative assessment is imperative to ensure appropriate clinical management. [ABSTRACT FROM AUTHOR]

Lung cancer is the main cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) being the predominant subtype. At present, immunotherapy represented by immune checkpoint inhibitors (ICIs) of programmed cell death receptor 1 or its ligand has been widely used in the clinical diagnosis and treatment of patients with NSCLC. However, only a few patients can benefit from it, and reliable predictive markers for immunotherapy are lacking. Radiomics is a tool that uses computer software and algorithms to extract a large amount of quantitative information from biomedical images. A large number of studies have confirmed that the radiomic model that predicts the immune efficacy of NSCLC can be used as a new type of immune efficacy predictive marker, which is expected to guide the individualized diagnosis and treatment decisions for patients with lung cancer and has a bright application prospect. This article reviews the research progress of radiomics in predicting the immune therapy response of NSCLC, identifying pseudo-progression and hyperprogression, ICIs-related pneumonia, cachexia risk, and combining with other genomics. [ABSTRACT FROM AUTHOR]

Immunotherapy has become the cornerstone of current malignant tumor treatment. However, the response of different patients to immunotherapy is highly heterogeneous, and not all patients can benefit from it. There is an urgent need to find biomarkers that can effectively predict the efficacy of immunotherapy. C-C chemokine ligand 4 (CCL4) is a cytokine, belonging to the inflammatory CCL subfamily. It is mainly secreted by immune cells and tumor cells and shows low or no expression in normal tissues but abnormally high expression in various malignant tumor tissues. After binding to CCL4 and its receptor C-C chemokine receptor type 5 (CCR5), it can recruit and mediate immune cell migration, destroy the stability of the tumor microenvironment (TME), participate in carcinogenesis and promote the development of tumors. In the tumor immune microenvironment, CCL4 can mediate and recruit the directed migration of key immune cells such as monocytes, macrophages, natural killer (NK) cells, and T cells, which makes it a potentially important element affecting the efficacy of immunotherapy and has specific value. This paper reviews the research progresses of CCL4's effects on immune escape in TME, in order to provide clues and references for basic research and clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: The chemokine receptor CXCR6 is critical for sustained tumor control mediated by CD8+ cytotoxic T cells (CTLs) in tumors. Previous studies have shown that ionizing radiation induces an inflamed immune contexture by upregulating CXCR6. However, the clinical significance of CXCR6 expression in triple-negative breast cancer (TNBC) and its correlation with radiotherapy remains unknown. This study aimed to clarify the prognostic value of CXCR6 and its role in the breast tumor microenvironment (TME). Methods: The messenger RNA and protein expression of CXCR6 in human TNBC and their association with survival were analyzed. The role of CXCR6 in the immune context was investigated using a combination of single-cell RNA sequencing, bulk transcriptome sequencing data, and fluorescence-based multiplex immunohistochemistry (mIHC) techniques. Results: Elevated CXCR6 expression correlated with better clinical outcomes and superior response to adjuvant radiotherapy and immunotherapy in TNBC. CXCR6 fostered an immunostimulatory microenvironment characterized by upregulated cytotoxic markers. We also found that CXCR6 plays a crucial role in regulating the differentiation of CD8+ T cells and the intercellular communication of immune cell subtypes, thus shaping the TME. Conclusions: This study highlights the emerging role of CXCR6 in shaping the TME and targeting CXCR6 may be a promising strategy for improving the effectiveness of radiotherapy and immunotherapy in TNBC. [ABSTRACT FROM AUTHOR]

[Display omitted] • This article focuses on immunotherapy, a new treatment for tumors with low side effects, and suggests the direction of improvement. • Programmed cell death (apoptosis, necroptosis, ferroptosis, pyroptosis and autophagy) induced by nanomedicine was reviewed in this paper. • This paper focuses on the role of nanomedicine-induced programmed cell death in cancer therapy. • This article reviews the improvement of the limitations of immunotherapy with nanomedicine-induced PCD. • In this paper, the development prospect of tumor therapy and immunotherapy of PCD mediated by nanomedical drugs is prospected. There has been widespread concern about the high cancer mortality rate and the shortcomings of conventional cancer treatments. Immunotherapy is a novel oncology therapy with high efficiency and low side effects, which is a revolutionary direction for clinical oncology treatment. However, its clinical effectiveness is uneven. Based on the redefinition and reclassification of programmed cell death (PCD) (divided into necroptosis, ferroptosis, pyroptosis, and autophagy), the role of nanomedicine-induced PCD in cancer therapy has also received significant attention. Clinical and preclinical studies have begun to combine PCD with immunotherapy. In this article, we present recent research in tumor immunotherapy, provide an overview of how nanomedicine-induced PCD is involved in tumor therapy, and review how nanomedicine-induced PCD can improve the limitations of immunotherapy to enhance tumor immunotherapy. The future development of nanomedicine-mediated PCD tumor therapy and tumor immunotherapy is also proposed Key scientific concepts of overview Nanomedicine-induced PCD is a prospective method of tumor immunotherapy. Nanomedicines increase tumor site penetration and targeting ability, and nanomedicine-mediated PCD activation can stimulate powerful anti-tumor immune effects, which has a good contribution to immunotherapy of tumors. [ABSTRACT FROM AUTHOR]

Analysis of rechallenge with nivolumab as 5th-line therapy for locally and nodally failed laryngeal squamous cell carcinoma following conventional therapeutic modalities: radiotherapy, surgery and chemotherapy. A 70-year-old male, with local and nodal progression of laryngeal squamous cell carcinoma after treatment with chemoradiotherapy and surgery, was initially treated for recurrence with carboplatin, 5-fluorouracile (FU) and cetuximab, followed by second-line nivolumab, and then two lines of conventional chemotherapy with paclitaxel and cetuximab followed by carboplatin and cetuximab. He underwent rechallenge with nivolumab in 5th line, achieving 12 months' response, ongoing at the time of writing, and 42.5 months' survival since initiation of exclusive systemic management after failure of conventional treatment. This case report highlights the benefit of nivolumab rechallenge in 5th line following previous failure as stand-alone therapy in 2nd line for a patient with laryngeal squamous cell carcinoma locally and nodally uncontrolled after conventional treatment. Clinical trials evaluating the efficacy of this approach are necessary to assess its contribution, as it is currently not a standard therapeutic option. [ABSTRACT FROM AUTHOR]

Due to the insufficient Cu+ accumulation, Cu+ efflux mechanism, and highly immunosuppressive tumor microenvironment (TME) in lung metastasis, the cuproptosis efficacy is limited. Herein, an inhalable nanodevice (CLDCu) is constructed to successfully overcome the drawbacks of cuproptosis. CLDCu consists of a Cu2+-chitosan shell and low molecular weight heparin-tocopherol succinate (LMWH-TOS, LT) core with disulfiram (DSF) loading. The prepared CLDCu can be inhaled and accumulate in large amounts in lung lesions (63.6%) with 56.5 times higher than intravenous injection. Within tumor cells, the mild acidity triggers the co-release of DSF and Cu2+, thus generating bis(diethyldithiocarbamate)-copper (CuET) to block Cu+ efflux protein ATP7B and forming toxic Cu+, leading to enhanced cuproptosis. Meanwhile, the released chitosan cooperates with CLDCu-induced cuproptosis to activate stimulator of interferon genes (STING) pathway, which significantly potentiates dendritic cells (DCs) maturation, as wells as evokes innate and adaptive immunity. In lung metastatic mice model, CLDCu is found to induce cuproptosis and reverse the immunosuppressive TME by inhalation administration. Moreover, CLDCu combined with anti-programmed cell death protein ligand-1 antibody (aPD-L1) provokes stronger antitumor immunity. Therefore, nanomedicine that combines cuproptosis with STING activation is a novel strategy for tumor immunotherapy. An inhalable nanoformulation (CLDCu) co-delivering disulfiram and Cu2+ was designed to enhance lung metastasis immunotherapy via cuproptosis and cGAS–STING activation. Moreover, CLDCu collaborated with aPD-L1 provoked more powerful antitumor immunity. [Display omitted] [ABSTRACT FROM AUTHOR]

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells. Herein, we constructed a PEGylated dendritic epirubicin (Epi) prodrug (Epi-P4D) to regulate the metabolism of cancer-associated fibroblasts (CAFs), thus enhancing Epi penetration into both multicellular tumor spheroids (MTSs) and tumor tissues in mouse colon cancer (CT26), mouse breast cancer (4T1) and human breast cancer (MDA-MB-231) models. Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin, α -SMA, and collagen secretion. Besides, thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell (DC) maturation and subsequent immune activation, including elevating the CD4+ T cell population, reducing CD4+ and CD8+ T cell hyperactivation and exhaustion, and amplifying the natural killer (NK) cell proportion and effectively activating them. As a result, this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy. A dendritic polymer-based nanomedicine was constructed to disturb the amino acid metabolism of cancer-associated fibroblasts for enhancing Epi penetration, boosting tumor immune cell infiltration, and elevating its therapeutic effect. [Display omitted] [ABSTRACT FROM AUTHOR]

Atezolizumab/bevacizumab combination therapy became the first-line therapy for advanced hepatocellular carcinoma (HCC). Gastroesophageal varices should be monitored and managed before treatment. The progression of portal hypertension during bevacizumab-containing therapy is unclear. A case of new development of esophageal varices, ascites, and hepatic hydrothorax during atezolizumab/bevacizumab therapy at National Taiwan University Hospital was reported, and relevant literature was reviewed. We presented an 83-year-old male with resolved hepatitis B without cirrhosis. He had BCLC stage C HCC and received tri-weekly atezolizumab/bevacizumab therapy for 34 cycles with sustained partial response. Progressive ascites, esophageal varices, and hepatic hydrothorax developed, though his portal vein was patent and the tumor was under control. Five similar cases of HCC (BCLC B/C: n = 3/2) had been reported previously. Among them, three had cirrhosis with pre-existing small esophageal varices before treatment. After the administration of 1–15 cycles of atezolizumab/bevacizumab therapy, one patient had a progression of varices, and the other four developed variceal bleeding. The association between atezolizumab/bevacizumab and portal hypertension was possible, which might relate to the VEGF pathway and immune-related adverse events with progressive hepatic fibrosis. Atezolizumab/bevacizumab treatment might exacerbate portal hypertension. Careful monitoring and management should be considered during treatment. [ABSTRACT FROM AUTHOR]

A first‐in‐human trial demonstrated that a vaccine targeting the histone mutation H3K27M can induce an immune response, in a mutation‐specific manner, in patients with diffuse midline glioma. In a recent study by Boschert et al., the same group now dissects the functional immune response triggered after effective vaccination of one of the patients, who has been in remission for over 3 years. The H3K27M peptide vaccine, named H3‐vac, induces a CD4+ T‐cell‐specific immune response in this patient and expands the repertoire of polyclonal H3K27M‐specific T‐cell receptors. A clonal H3K27M‐reactive B‐cell population was also detected in the patient's cerebrospinal fluid. Importantly, the immune response is induced across various human leukocyte antigen alleleotypes, indicating the potential efficacy of the vaccine in diverse populations. By exploring in detail the immune response linked to this patient's long‐term survival, the authors prove peptide vaccinations as a viable therapeutic approach. This paves the way for personalised therapies harnessing immunogenic T‐ and B‐cell responses against different tumour types. [ABSTRACT FROM AUTHOR]

Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD‐1) have been proven to be an effective first‐line therapy against programmed cell death 1 ligand 1 (PD‐L1; also known as CD274 molecule)‐expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE‐048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12‐dimethylbenzanthracene into the buccal mucosa. Single‐cell suspension was isolated from tumor tissue; proliferating cells were injected subcutaneously into the left flank of mice to establish Ajou oral cancer (AOC) cell lines. Subsequently, a syngeneic PD‐L1‐expressing HNSCC model was developed by injecting AOC cells into the buccal or tongue area. The model recapitulated human HNSCC molecular features and showed reliable in vivo tumorigenicity with significant PD‐L1 expression. ICB monotherapy induced global changes in the TME, including vascular normalization. Furthermore, the antitumor effect of ICB monotherapy was superior to those of other therapeutic agents, including cisplatin and inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2). The ICB‐induced antitumorigenicity and TME normalization were alleviated by blocking the type I interferon pathway. In summary, ICB monotherapy is sufficient to induce TME normalization in the syngeneic model; the type I interferon pathway is indispensable in realizing the effects of ICBs. Furthermore, these results explain the underlying mechanism of the efficacy of ICB monotherapy against PD‐L1‐expressing HNSCC in the KEYNOTE‐048 trial. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR‐T) cell therapy is a newly developed immunotherapy strategy and has achieved satisfactory outcomes in the treatment of hematological malignancies. However, some adverse effects related to CAR‐T cell therapy have to be resolved before it is widely used in clinics as a cancer treatment. Furthermore, the application of CAR‐T cell therapy in the treatment of solid tumors has been hampered by numerous limitations. Therefore, it is essential to explore novel strategies to improve the therapeutic effect of CAR‐T cell therapy. In this review, we summarized the recently developed strategies aimed at optimizing the generation of CAR‐T cells and improving the anti‐tumor efficiency of CAR‐T cell therapy. Furthermore, the discovery of new targets for CAR‐T cell therapy and the combined treatment strategies of CAR‐T cell therapy with chemotherapy, radiotherapy, cancer vaccines and nanomaterials are highlighted. [ABSTRACT FROM AUTHOR]

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti‐programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C‐C motif chemokine 5 (CCL5) and C‐X‐C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34‐dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti‐tumor response. We showed that VPS34 inhibitors increased the secretion of T‐cell‐recruitment chemokines in a cyclic GMP‐AMP synthase (cGAS)/stimulator of interferon genes protein (STING)‐dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)‐mediated VPS34 inhibition increased cGAS/STING‐mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16‐F10 tumor‐bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune‐mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway. [ABSTRACT FROM AUTHOR]

Copyright of Revista Colombiana de Gastroenterología is the property of Asociacion Colombiana de Gastroenterologia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8+ T cell in SCCE for the first time. Materials and methods: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. Results: No patients had PD-L1 expressed in their tumor cells. PD-L1+ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68+ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapsefree survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (Ptrend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. Conclusion: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy. [ABSTRACT FROM AUTHOR]