Breast cancer (BC) is the most commonly diagnosed cancer in women. N6-methyladenosine (m6A) is the most prevalent internal modification in mammalian mRNAs and plays a crucial role in various biological processes. However, its function in Natural killer (NK) cells in BC remains unclear. NK cells are essential for cancer immunosurveillance. This study aims to assess m6A levels in transcripts involved in the NKG2D cytotoxicity signaling pathway in NK cells of BC patients compared to controls and find out its impact on mRNA levels. Additionally, it evaluates how deliberately altering m6A levels in NK cells affects mRNA and protein expression of NKG2D pathway genes and NK cell functionality.

m6A methylation in transcripts of NKG2D-pathway-related genes in BC patients and controls was determined using methylated RNA immunoprecipitation-reverse transcription-PCR (MERIP-RT-PCR). To deliberately alter m6A levels in primary cultured human NK cells, the m6A demethylases, FTO and ALKBH5, were knocked out using the CRISPR-CAS9 system, and FTO was inhibited using Meclofenamic acid (MA). The impact of m6A alteration on corresponding mRNA and protein levels was assessed using RT-qPCR and Western blot analysis or flow cytometry, respectively. Additionally, NK cell functionality was evaluated through degranulation and 51Cr release cytotoxicity assays.

Transcripts of NKG2D, an activating receptor that detects stressed non-self tumour cells, had significantly higher m6A levels in the 3' untranslated region (3'UTR) accompanied by a marked reduction in their corresponding mRNA levels in BC patients compared to controls. Conversely, transcripts of ERK2 and PRF1 exhibited significantly lower m6A levels escorted with higher mRNA expression in BC patients relative to controls. The mRNA levels of PI3K, PAK1 and GZMH were also significantly elevated in BC patients. Furthermore, artificially increasing transcripts' m6A levels via MA in cultured primary NK cells reduced mRNA levels of NKG2D pathway genes and death receptor ligands but did not affect protein expression or NK cell functionality.

Transcripts with higher m6A levels in the 3'UTR region were less abundant, and vice versa. However, changes in mRNA levels of the target genes didn't impact their corresponding protein levels or NK cell functionality.

We present a model-free phase I/II clinical trial design, referred to as the UFO design, to optimize the dose of immunotherapy by jointly modeling toxicity, efficacy, and immune response outcomes. Instead of relying on complex parametric modeling approaches, we propose a model-free approach that uses the inherent correlations among different types of outcomes in immunotherapy and the constrained dose-outcome order to facilitate information sharing across different doses. This approach ensures the efficiency and transparency of the UFO design to be implemented in clinical practice. The UFO design is also extended to accommodate the delayed outcomes. It demonstrates favorable operating characteristics through simulation studies. The R Shniy app for simulation and trial implementation using the UFO design is also provided at iusccc.shinyapps.io/smartdesign.

T cells and their T cell receptors (TCRs) play crucial roles in the adaptive immune system's response against pathogens and tumors. However, immunosenescence, characterized by declining T cell function and quantity with age, significantly impairs antitumor immunity. Recent years have witnessed remarkable progress in T cell-based cancer treatments, driven by a deeper understanding of T cell biology and innovative screening technologies. This review comprehensively examines T cell maturation mechanisms, T cell-mediated antitumor responses, and the implications of thymic involution on T cell diversity and cancer prognosis. We discuss recent advances in adoptive T cell therapies, including tumor-infiltrating lymphocyte (TIL) therapy, engineered T cell receptor (TCR-T) therapy, and chimeric antigen receptor T cell (CAR-T) therapy. Notably, we highlight emerging DNA-encoded library technologies in mammalian cells for high-throughput screening of TCR-antigen interactions, which are revolutionizing the discovery of novel tumor antigens and optimization of TCR affinity. The review also explores strategies to overcome challenges in the solid tumor microenvironment and emerging approaches to enhance the efficacy of T cell therapy. As our understanding of T cell biology deepens and screening technologies advances, T cell-based immunotherapies show increasing promise for delivering durable clinical benefits to a broader patient population.

Antigen-presenting cells (APCs), such as macrophages and dendritic cells (DCs) are key players in modulating the immune responses of cytotoxic T lymphocytes (CTLs). Resiquimod (R848), a toll-like receptor (TLR) agonist, has demonstrated the capacity to enhance APC function and reprogram the phenotype of macrophages; however, the unfavorable in vivo performance constrains its therapeutic potential. Here, we developed R848-loaded mesoporous silica nanoparticles (denoted as R848@MSN-bi-PEG) with pH-responsive surface polyethylene glycol (PEG) detachment to effectively modulate APCs. The acidic tumor pH triggered PEG detachment when R848@MSN-bi-PEG accumulated at the tumor site, thereby promoting APC uptake and R848 release, which facilitated DCs maturation and macrophage repolarization to a pro-inflammatory phenotype. The in vivo antitumor study indicated that R848@MSN-bi-PEG led to potent anti-tumor immunity by modulating the immunosuppressive tumor microenvironment. This approach offers a novel strategy to improve the effectiveness of cancer immunotherapy.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has been recognized as a promising target for cancer immunotherapy. Although various STING agonists have been developed, their clinical applications are still severely impeded by various issues, such as non-specific accumulation, adverse effects, rapid clearance, etc. In recent years, the emergence of nanomaterials has profoundly revolutionized STING agonists delivery, which promote tumor-targeted delivery, boost the immunotherapeutic effects and reduce systemic toxicity of STING agonists. In particular, polymer nanomaterials possess inherent advantages including controllable structure, tunable function and degradability. These properties afford them the capacity to serve as delivery vehicles for small-molecule STING agonists. Furthermore, the superior characteristics of polymer nanomaterials can enable their utilization as a novel STING agonist to stimulate anti-tumor immunity. In this review, the molecular mechanisms of cGAS-STING pathway activation are discussed. The recent development of small-molecules STING agonists is described. Then polymer nanomaterials are discussed as carriers for STING agonists in cancer immunotherapy, including polymersomes, polymer micelles, polymer capsules, and polymer nanogels. Additionally, polymer nanomaterials are identified as a novel class of STING agonists for efficient cancer immunotherapy, encompassing both polymer materials and polymer-STING agonists conjugates. The review also presents the combination of polymer-based cGAS-STING immunotherapy with chemotherapy, radiotherapy, phototherapy (both photodynamic and photothermal), chemodynamic therapy, and other therapeutic strategies. Furthermore, the discussion highlights recent advancements targeting the cGAS-STING pathway in clinically approved polymer nanomaterials and corresponding potent innovations. Finally, the potential challenges and perspectives of polymer nanomaterials for activating cGAS-STING pathway are outlined, emphasizing the critical scientific issue and hoping to offer guidance for their clinical translation.

B7-H4 functions as an immune checkpoint in the tumor microenvironment (TME). However, the post-translational modification (PTM) of B7-H4 and its translational potential in cancer remains incompletely understood. We find that ZDHHC3, a zinc finger DHHC-type palmitoyltransferase, palmitoylates B7-H4 at Cys130 in breast cancer cells, preventing its lysosomal degradation and sustaining B7-H4-mediated immunosuppression. Knockdown of ZDHHC3 in tumors results in robust anti-tumor immunity and reduces tumor progression in murine models. Moreover, abemaciclib, a CDK4/6 inhibitor, primes lysosome activation and promotes lysosomal degradation of B7-H4 independently of the tumor cell cycle. Treatment with abemaciclib results in T cell activation and mitigates B7-H4-mediated immune suppression via inducing B7-H4 degradation in preclinical tumor models. Thus, B7-H4 palmitoylation is an important PTM controlling B7-H4 protein stability and abemaciclib may be repurposed to promote B7-H4 degradation, thereby treating patients with B7-H4 expressing tumors.

In situ personalized tumor vaccines are produced directly at the primary tumor site by killing cancer cells and stimulating immune cells, they are effective against individuals and bypass the complexity and high cost of in vitro vaccine production. However, their clinical application is hindered by insufficient efficiency in inducing immunogenic cancer cell death (ICD) and systemic inflammation caused by immune adjuvants. Here, personalized cancer vaccines are constructed in situ for melanoma immunotherapy based on bioorthogonal catalytic microneedles, which enable the catalytic release of prodrugs at tumor sites and mediate strong ICD and an enhanced tumor immune response while avoiding systemic immune storms and toxic side effects. By incorporating TiO2 nanosheets supported Pd into swellable microneedles, the bioorthogonal microneedles are constructed to catalyze the depropargylation reaction of doxorubicin (DOX) prodrug and imiquimod (IMQ) prodrug in situ. The activated DOX at subcutaneous tumor sites induced strong ICD and released tumor-associated antigens. Concurrently, the activated IMQ acts as a Toll-like receptor (TLR7) agonist, enhancing the anti-tumor immune response. In vivo experiments demonstrate that this immunotherapy achieves ≈97% inhibition of primary tumors and effectively inhibits untreated distant tumors (≈94% inhibition) and lung metastasis (≈92% inhibition).

Immunotherapy is the concept of leveraging the immune system to treat diseases. Developing countries, including the Arab countries, have continued to lag in terms of biomedical research compared to other nations for several decades. Immunotherapy has been used in several fields, including cancer, transplantation, and vaccination. This article examined the activity and trend of immunotherapy research in the Arab world between 2000 and 2024.

The number of immunotherapy-related articles published by each Arab country, was assessed using the PubMed database between 2000 and 2024. Numbers were normalized with respect to each country's average population and average Gross Domestic Product (GDP).

Arab countries contributed to 1.73 % of total immunotherapy papers. The number of immunotherapy publications has grown from 2000 to 2022, then decreased in the past 2 years. In terms of publications per million persons, Qatar ranked first (130.08 per million persons), while in terms of publications per national GDP, Lebanon ranked first (11.09 per billion US dollars). MeSH keywords VOSviewer showed a focus on vaccination, COVID-19, COVID-19 vaccines, and transplantation conditioning in the Arab world.

This bibliometric analysis provides insight into the actualities and trends of immunotherapy research in the Arab world. This offers a general background for scientists, clinicians, funders, and decision-makers. Addressing the barriers that face immunotherapy research remains a cornerstone in the plan to improve the Arab world's output and contribution to this field.

Among the leading methods for triggering therapeutic anti-cancer immunity is the inhibition of immune checkpoint pathways. N-glycosylation is found to be essential for the function of various immune checkpoint proteins, playing a critical role in their stability and interaction with immune cells. Removing the N-glycans of these proteins seems to be an alternative therapy, but there is a lack of a de-N-glycosylation technique for target protein specificity, which limits its clinical application. Here, we developed a novel technique for specifically removing N-glycans from a target protein on the cell surface, named deglycosylation targeting chimera (DGlyTAC), which employs a fusing protein consisting of Peptide-N-glycosidase F (PNGF) and target-specific nanobody/affibody (Nb/Af). The DGlyTAC technique was developed to target a range of glycosylated surface proteins, especially these immune checkpoints-CD24, CD47, and PD-L1, which minimally affected the overall N-glycosylation landscape and the N-glycosylation of other representative membrane proteins, ensuring high specificity and minimal off-target effects. Importantly, DGlyTAC technique was successfully applied to lead inactivation of these immune checkpoints, especially PD-L1, and showed more potential in cancer immunotherapy than inhibitors. Finally, PD-L1 targeted DGlyTAC showed therapeutic effects on several tumors in vivo, even better than PD-L1 antibody. Overall, we created a novel target-specific N-glysocylation erasing technique that establishes a modular strategy for directing membrane proteins inactivation, with broad implications on tumor immune therapeutics.

Innate and adaptive immune responses serve a crucial role in neoplasms. The interaction of immune cells with the neoplastic tissue influences tumor behavior, resulting in either pro-tumorigenic or anti-tumorigenic effects. However, the prognostic significance of the tumor immune microenvironment (TIME) in synovial sarcoma (SS) remains poorly studied. This study aimed to analyze the TIME of SS to determine its impact on the prognosis by examining the intratumoral lymphocytic and macrophagic infiltrate and its potential correlation with survival and recurrence.

We conducted a retrospective observational study of 49 fusion-confirmed SS cases collected from two different institutions. We obtained clinical and follow-up data, and SSs were histologically classified according to WHO criteria. Immunohistochemical analysis, including of CD163, CD68, CD3, CD8, and CD20, was conducted in tissue microarrays using an analog scale. We examined the whole-slide tissue for the 23 cases with sufficient material available and then assessed the positive area by scanning the slides and analyzing the images using QuPath (0.4.4, Belfast, Northern Ireland) to calculate the positive area in an immune hotspot. We correlated the expression of these markers with clinical outcomes. A log-rank test and Kaplan-Meyer curves were used as appropriate (significance: p ≤ 0.05).

The most frequent morphological subtype was monophasic (59.6%), followed by biphasic (26.9%) and undifferentiated (7%). The mean disease specific survival (DSS) was 55.3 months, with a median of 33 months. The median overall survival (OS) was 50 months (range: 2-336 months). Both evaluation methods showed a good correlation for all antibodies, with Chi-square values of p < 0.05. All cases showed variable amounts of CD163-positive macrophages. The cases that showed a higher density of CD163-positive macrophages in whole-slide images subjected to digital analysis demonstrated an improved OS and DSS on Kaplan-Meier curves. Cases with lower CD8 and CD3 positivity showed a tendency toward faster progression and a slightly worse prognosis.

The tumor immune microenvironment in sarcomas is a complex system that requires further investigation to fully understand its impact on tumorigenesis and patient clinical outcomes. Our results demonstrate that a higher amount of intratumoral CD163-positive macrophage infiltrate is associated with an increased OS and DSS. Our findings show that digital pathology is more precise than subjective quantitative analysis.

Cancer immunotherapy has been transformed by chimeric antigen receptor (CAR) T-cell treatment, which has shown groundbreaking results in hematological malignancies. However, its application in solid tumors remains a formidable challenge due to immune evasion, tumor heterogeneity, and safety concerns arising from off-target effects. A long-standing effort in this field has been the development of synthetic receptors to create new signaling pathways and rewire immune cells for the specific targeting of cancer cells, particularly in cell-based immunotherapy. This field has undergone a paradigm shift with the introduction of synthetic Notch (synNotch) receptors, which offer a highly versatile signaling platform modeled after natural receptor-ligand interactions. By functioning as molecular logic gates, synNotch receptors enable precise, multi-antigen regulation of T-cell activation, paving the way for enhanced specificity and control. This review explores the revolutionary integration of synNotch systems with CAR T-cell therapy, emphasizing cutting-edge strategies to overcome the inherent limitations of traditional approaches. We delve into the mechanisms of synNotch receptor design, focusing on their ability to discriminate between cancerous and normal cells through spatiotemporally controlled gene expression. Additionally, we highlight recent advancements to improve therapeutic efficacy, safety, and adaptability in treating solid tumors. This study highlights the potential of synNotch-based CAR-T cells to transform the field of targeted cancer therapy by resolving present challenges and shedding light on potential future paths.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Since the first approval of an immune checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.

As the seventh-leading contributor to global cancer-related deaths, esophageal cancer (EC) is one of the most challenging types of cancer. Despite advancements in conventional therapies, including surgery, chemotherapy, and radiotherapy, the five-year survival rate remains low, underscoring the need for the development of more efficacious treatment approaches. Immunotherapy has emerged as a promising treatment approach, offering new hope for EC patients. This review provides an in-depth examination of the latest immunotherapeutic strategies for EC, focusing on immune checkpoint inhibitors, adoptive cell therapy, cancer vaccines, and oncolytic virotherapy. We critically analyze the current clinical data to highlight the progress and pitfalls of each immunotherapeutic approach for EC. Additionally, we explore the potential for combination therapies, which could overcome the resistance often seen with monotherapies. Finally, we discuss the limitations of current treatments and outline key areas for future research to improve patient outcomes and survival.

Today, treating cancer patients with monoclonal antibodies (mAbs), by targeting immune checkpoints, is one of the most outstanding immunotherapeutic methods. Immune checkpoints are special molecules having regulatory role in immune system responses. Once these molecules are presented on cancer cells, these cells will be capable of evading the immune system through their own specific pathways. This Evasion can be prevented by counterbalancing immune system responses with immune checkpoints related antibodies.

The current study aimed to highlight immunotherapy and its methods, describe the immune checkpoints pathways, outline the immune checkpoint inhibitors (ICIs), and recent advances in this field, and sketch an outlook on the best treatment options for the most prevalent cancers.

This research implemented a narrative review method. A comprehensive literature review on the history, molecular and cellular biology, and the clinical aspects of immune checkpoint molecules was performed to illustrate the pathways involved in various cancers. Also, currently-available and future potential immunotherapies targeting these pathways were extracted from the searched studies.

The immune checkpoint family consists of many molecules, including CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, and TIGIT. Attempts to modify these molecules in cancer treatment led to the development of therapeutic monoclonal antibodies. Most of these antibodies have entered clinical studies and some of them have been approved by the Food and Drug Administration (FDA) to be used in cancer patients' treatment plans.

With these novel treatments and the combination therapies they offer, there is also hope for better treatment outcomes for the previously untreatable metastatic cancers. In spite of the beneficial aspects of immune checkpoint therapy, similar to other treatments, they may cause side effects in some patients. Therefore, more studies are needed to reduce the probable side effects and uncover their underlying mechanism.

Based on the data shown in this review, there is still a lack of knowledge about the complete properties of ICIs and the possible combination therapies that we may be able to implement to achieve a better treatment response in cancer patients.

Remodeling the immunosuppressive tumor microenvironment (TME) by immunomodulators has been well studied in the past years. However, strategies that enable concurrent modulation of both the immunosuppressive TME and tumor-draining lymph nodes (TDLNs) are still in the infancy. Here, we report a pH-sensitive size-switchable nanocluster, SPN-R848, to achieve simultaneous accumulation in tumor and TDLNs for immune activation. SPN-R848 with original size around 150 nm was formed by self-assembly of resiquimod (R848)-conjugated polyamidoamine (PAMAM) derivative, which could disintegrate into its small constituents (～ 8 nm) upon exposure to tumor acidity. The size reduction not only enhanced their accumulation and perfusion in the primary tumor, but promoted their transport and distribution in TDLNs. Accordingly, SPN-R848 remarkably remodeled the immunosuppressive TME by polarizing M2 to M1 macrophages and activated dendritic cells (DCs) in TDLNs, which synergistically facilitated the production and stimulation of cytotoxic T cells, and inhibited tumor growth in breast cancer and melanoma mouse models. Our study suggests that co-activation of immune microenvironments in both tumor and TDLNs may represent a promising direction to elicit strong antitumor immunity.

Cancer is the second-highest cause of death worldwide. Accordingly, finding new cancer treatments is of great interest to researchers. The current platforms to fight cancer such as chemotherapy, radiotherapy, and surgery are limited in efficacy, especially in the metastatic setting. In this war against cancer, the immune system is a powerful ally, but tumor cells often outsmart it through alternative pathways. Cluster of differentiation 47 (CD47), a protein that normally prevents healthy cells from being attacked by immune cells, is often overexpressed on cancer cells. This makes CD47 a prime target for immunotherapy. Blocking of CD47 has the potential to unleash the immune system's cell populations-such as myeloid cells, macrophages, and T cells-to allow the immune system to discover and destroy cancer cells more successfully. In this review, we aimed to provide the latest information and findings about the roles of CD47 in the regulation of various cellular pathways and, thus, the importance of CD47 as a potential target in cancer therapy.

Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment, yet their impact on bone health remains unclear. This study aimed to perform a retrospective cohort study utilizing routine CT scans from patients with melanoma to perform opportunistic QCT analysis to investigate the effects of ICI treatment on skeletal health, including volumetric BMD (vBMD) measurements and osteoarthritis (OA) parameters. A previously established machine learning-assisted opportunistic QCT pipeline was used to estimate lumbar spine vBMD from baseline and 12-mo follow-up CT scans in patients with melanoma treated with ICI therapy and those not treated with ICI therapy. Facet joint OA, osteophyte formation, and endplate sclerosis were also graded. Independent and paired t tests were used to determine any differences in vBMD and OA parameters between ICI users and non-ICI users. Multivariable linear regression models were used to control for confounding variables. Non-ICI users had a significant decrease in vBMD of -6.96 mg/cm3 from baseline to follow-up, whereas the ICI users had no significant change. There was a significant difference in change in vBMD from baseline to follow-up between the 2 groups, with the non-ICI users experiencing a 11.22 mg/cm3 larger decrease in vBMD. After adjusting for baseline age, sex, baseline vBMD, and change in OA parameters, this difference remained significant at -13.04 mg/cm3. Among the ICI users, those who had a decline in vBMD had a lower baseline vBMD compared with those who had increased vBMD. Neither group showed a significant change in OA parameters over the follow-up period, nor a difference in change between ICI and non-ICI users, even after adjusting for sex, age, and baseline OA parameters. While the effects of ICI treatment on vBMD may vary based on baseline bone health, ICIs do not significantly impact OA parameters in the short term.

Immune checkpoint inhibitor (ICI) therapies have revolutionized cancer therapy and improved patient outcomes in a range of cancers. ICIs enhance anti-tumour immunity by targeting the inhibitory checkpoint receptors CTLA-4, PD-1, PD-L1, and LAG-3. Despite their success, efficacy, and tolerance vary between patients, raising new challenges to improve these therapies. These could be addressed by the identification of robust biomarkers to predict patient outcome and a more complete understanding of how ICIs affect and are affected by the tumour microenvironment (TME). Despite being the first ICIs to be introduced, anti-CTLA-4 antibodies have underperformed compared with antibodies that target the PD-1/PDL-1 axis. This is due to the complexity regarding their precise mechanism of action, with two possible routes to efficacy identified. The first is a direct enhancement of effector T-cell responses through simple blockade of CTLA-4-'releasing the brakes', while the second requires prior elimination of regulatory T cells (TREG) to allow emergence of T-cell-mediated destruction of tumour cells. We examine evidence indicating both mechanisms exist but offer different antagonistic characteristics. Further, we investigate the potential of the soluble isoform of CTLA-4, sCTLA-4, as a confounding factor for current therapies, but also as a therapeutic for delivering antigen-specific anti-tumour immunity.

Photodynamic therapy is an "old" strategy for cancer therapy featuring clinical safety and rapid working, but suitable photosensitizers for colorectal cancer therapy remain lacking. This study synthesized a novel photosensitizer termed Ce6-GFFY based on a self-assembling peptide GFFY and a photo-responsive molecule chlorin e6 (Ce6). Ce6-GFFY forms macroparticles with a diameter of ∼160 nm and possesses a half-life of 10 h, as well as an ideal tumor-targeting ability in mouse models. Ce6-GFFY effectively penetrates cells and generates numerous reactive oxygen species upon 660 nm laser irradiation. The reactive oxygen species promotes the accumulation of cytotoxic T cells and decrease of myeloid-derived suppressor cells in the tumor microenvironment through immunogenic cell death, thus prohibiting the growth of both primary and metastatic tumors after once treatment. This study not only provides a strategy for photosensitizer development but also confirms a promising application of Ce6-GFFY for colorectal cancer therapy.

Racial differences in antitumoral immunity have been identified in a variety of cancers and may contribute to survival disparities, but limited data exist exploring the molecular differences in pancreatic adenocarcinoma (PDAC). Using racially diverse PDAC datasets, we explored biologic differences that may drive disparities between African American (AA) and European American (EA) PDAC patients.

Genomic PDAC mutational data was analyzed for mutational differences based on race. In a separate cohort, surgical PDAC specimens were processed for both tissue microarray and multiplex gene expression analysis using NanoString.

Of the 4679 patient samples in the mutational dataset, AA PDAC patients had significantly more TP53 mutations compared to the EA cohort. The tissue microarray included 12 AA and 41 EA surgically resected treatment-naive PDAC samples. NanoString analysis revealed significant differences between AA and EA groups in immunologic gene annotations (P < 0.05).

In the present study, we demonstrated that across racially diverse datasets, there exist molecular and microenvironmental differences between AA and EA patients that may contribute to cancer survival disparities. Defining molecular differences underlying PDAC racial disparities is an essential step in advancing care and improving outcomes for AA patients that suffer worse survival across cancer types.

The emergence of precision cancer treatment has triggered a paradigm shift in the field of oncology, facilitating the implementation of more effective and personalized therapeutic approaches that enhance patient outcomes. The pH of the tumor microenvironment (TME) plays a pivotal role in both the initiation and progression of cancer, thus emerging as a promising focal point for precision cancer treatment. By specifically targeting the acidic conditions inherent to the tumor microenvironment, innovative therapeutic interventions have been proposed, exhibiting significant potential in augmenting treatment efficacy and ameliorating patient prognosis. The concept of ultra-pH-sensitive (UPS) nanoplatform was proposed several years ago, demonstrating exceptional pH sensitivity and an adjustable pH transition point. Subsequently, diverse UPS nanoplatforms have been actively explored for biomedical applications, enabling the loading of fluorophores, therapeutic drugs, and photosensitizers. This review aims to elucidate the design strategy and response mechanism of the UPS nanoplatform, with a specific emphasis on its applications in surgical therapy, immunotherapy, drug delivery, photodynamic therapy, and photothermal therapy. The potential and challenges of translating in the clinic on UPS nanoplatforms are finally explored. Thanks to its responsive and easily modifiable nature, the integration of multiple functional units within a UPS nanoplatform holds great promise for future advancements in tumor precision theranositcs.

Multistate models have been widely applied in health technology assessment. However, extrapolating survival in a multistate model setting presents challenges in terms of precision and bias. In this article, we develop an individual-level continuous-time multistate model that integrates relative survival extrapolation and mixed time scales.

We illustrate our proposed model using an illness-death model. We model the transition rates using flexible parametric models. We update the hesim package and the microsimulation package in R to simulate event times from models with mixed time scales. This feature allows us to incorporate relative survival extrapolation in a multistate setting. We compare several multistate settings with different parametric models (standard vs. flexible parametric models), and survival frameworks (all-cause vs. relative survival framework) using a previous clinical trial as an illustrative example.

Our proposed approach allows relative survival extrapolation to be carried out in a multistate model. In the example case study, the results agreed better with the observed data than did the commonly applied approach using standard parametric models within an all-cause survival framework.

We introduce a multistate model that uses flexible parametric models and integrates relative survival extrapolation with mixed time scales. It provides an alternative to combine short-term trial data with long-term external data within a multistate model context in health technology assessment.

Metastatic disease is the leading cause of cancer-related death, despite recent advances in therapeutic interventions. Prior modeling approaches have accounted for the adaptive immune system's role in combating tumors, which has led to the development of stochastic models that explain cancer immunoediting and tumor-immune co-evolution. However, cancer immune-mediated dormancy, wherein the adaptive immune system maintains a micrometastatic population by keeping its growth in check, remains poorly understood. Immune-mediated dormancy can significantly delay the emergence (and therefore detection) of metastasis. An improved quantitative understanding of this process will thereby improve our ability to identify and treat cancer during the micrometastatic period. Here, we introduce a generalized stochastic model that incorporates the dynamic effects of immunomodulation within the tumor microenvironment on T cell-mediated cancer killing. This broad class of nonlinear birth-death model can account for a variety of cytotoxic T cell immunosuppressive effects, including regulatory T cells, cancer-associated fibroblasts, and myeloid-derived suppressor cells. We develop analytic expressions for the likelihood and mean time of immune escape. We also develop a method for identifying a corresponding diffusion approximation applicable to estimating population dynamics across a wide range of nonlinear birth-death processes. Lastly, we apply our model to estimate the nature and extent of immunomodulation that best explains the timing of disease recurrence in bladder and breast cancer patients. Our findings quantify the effects that stochastic tumor-immune interaction dynamics can play in the timing and likelihood of disease progression. Our analytical approximations provide a method of studying population escape in other ecological contexts involving nonlinear transition rates.

Convincing evidence revealed that some platinum-based drugs could stimulate immunological recognition, thereby inducing immunogenic cell death (ICD). Indoleamine-2,3-dioxygenase (IDO) is overexpressed in tumors, which caused exhaustion of tryptophan (T-cell energy) and constructed an immunosuppressive tumor microenvironment. Herein, considering IDO inhibition to improve chemotherapy, a series of IDOi-Pt(IV) prodrugs were designed to not only target DNA and IDO but also facilitate tumor-antigen exposure and immunomodulation. The optimal IDOi-Pt(IV) prodrugs (named compound 10) significantly enhanced intracellular accumulation 22.4-fold and cytotoxicity 61.75-fold superior to cisplatin in HeLa cells. Moreover, immunofluorescence and enzyme-linked immunosorbent assays revealed that 10 induced reactive oxygen species-mediated endoplasmic reticulum stress and secretion of damage-associated molecular patterns, thereby presenting ICD effects. Molecular docking, enzyme inhibition, and Western blot assays demonstrated that 10 could effectively inhibit IDO1 and reverse immunosuppression, as further verified by mixed leukocyte reactions. In vivo tests showed that 10 exhibited high-efficiency and low-toxicity antitumor effects compared to cisplatin, presenting successful chemoimmunotherapy.

We examine the complex relationship between genomic copy number variation (CNV) and gene expression, highlighting the relevance to cancer biology and other biological contexts. By tracing the history of genometranscriptome correlations, we emphasize the complexity and challenges in understanding these interactions, particularly within the heterogeneous landscape of human cancers. Recent advances in computational algorithms and high-throughput single-cell multi-omic sequencing technologies are discussed, demonstrating their potential to refine our understanding of cancer biology and their limitations. The integration of genomic and transcriptomic analyses, which offers novel insights into tumor evolution and heterogeneity as well as therapeutic strategies, is presented as a crucial approach for advancing cancer research.

It is increasingly appreciated that the expression of immunoregulatory molecules within tumors have potential to shape a microenvironment that promotes local immunoevasion and immunoregulation. However, little is known about tissue-intrinsic immunomodulatory mechanisms following transplantation. We propose that differences in the phenotype of microvascular endothelial cells impact the alloantigenicity of the graft and its potential to promote immunoregulation following transplantation. We focus this review on the concept that graft-dependent immunoregulation may evolve post-transplantation, and that it is dependent on the phenotype of select subsets of intragraft endothelial cells. We also discuss evidence that long-term graft survival is critically dependent on adaptive interactions among immune cells and endothelial cells within the transplanted tissue microenvironment.

Bladder cancer is one of the most common malignancies worldwide. Standard neoadjuvant or metastatic therapy used to be cisplatin-based chemotherapy, but many patients are ineligible due to age, renal impairment, or frailty. Checkpoint inhibitors (e.g., atezolizumab and pembrolizumab) enhance survival in cisplatin-ineligible patients. Originally approved as second-line therapy for patients after platinum-based chemotherapy, nivolumab was approved by the FDA for adjuvant therapy of high-risk muscle-invasive urothelial cancer following the Checkmate 274 trial. It is indicated for patients with resected disease or cisplatin ineligibility. Recent developments focused on the contribution of nivolumab to outcomes have been complemented by ongoing investigations on atezolizumab as a monotherapy or in combinations for muscle-invasive bladder cancer, providing further hope for improved control. This narrative review aims to clarify the current applications of immunotherapy in treating bladder cancer and to explore the future outlook based on ongoing clinical trials.

Surgical resection is the most effective therapeutic option for the cure in early stage resectable non-small-cell lung cancer (NSCLC). However, despite complete resection, up to 70% of patients die within 5 years mainly due to tumor recurrence in extra-thoracic organs. Adjuvant or neoadjuvant platinum-based chemotherapy may improve postoperative survival, but the absolute survival benefit is modest with an around 5% improvement at 5 years. Recent advance in systemic therapy has changed treatment strategy for advanced unresectable NSCLC, and also has provided a paradigm shift in treatment strategy for resectable NSCLC. For NSCLC without oncogenic driver alterations, immunotherapy using immune-checkpoint inhibitors may improve clinical outcomes in preoperative neoadjuvant setting as well as in postoperative adjuvant setting. Here, we overview recent evidence of adjuvant and neoadjuvant therapy and discuss emerging clinical questions in decision-making of treatment for potentially resectable patients with NSCLC harboring no oncogenic alterations.

The established protocol for the management of acute myeloid leukemia (AML) has traditionally involved the administration of induction chemotherapy, followed by consolidation chemotherapy, and subsequent allogeneic stem cell transplantation for eligible patients. However, the prognosis for individuals with relapsed and refractory AML remains unfavorable. In response to the necessity for more efficacious therapeutic modalities, targeted immunotherapy has emerged as a promising advancement in AML treatment. This comprehensive review article specifically examines classical unconjugated and toxin-conjugated monoclonal antibodies, which are currently in the preclinical phase or undergoing evaluation in clinical trials. The review delves into the proposed mechanisms through which these monoclonal antibodies elicit anti-tumor activity and identifies the challenges associated with designing targeted immunotherapy. The review focuses on targeting specific antigens in AML, including FLT3/CD125, CLL-1, CD33, CD38, CD47, CD70, and CD123.

Antibody-based checkpoint inhibitors have achieved great success in cancer immunotherapy, but their uncontrollable immune-related adverse events remain a major challenge. In this study, we developed a tumor-activated nanoparticle that is specifically active in tumors but not in normal tissues. We discovered a short anti-PD-L1 peptide that blocks the PD-1/PD-L1 interaction. The peptide was modified with a PEG chain through a novel matrix metalloproteinase-2 (MMP-2)-specific cleavage linker. The modified TR3 peptide self-assembles into a micelle-like nanoparticle (TR3-M-NP), which remains inactive and unable to block the PD-1/PD-L1 interaction in its native form. However, upon cleavage by MMP-2 in tumors, it releases the active peptide. The TR3-M-NP5k nanoparticle was specifically activated in tumors through enzyme-mediated cleavage, leading to the inhibition of tumor growth and extended survival compared to control groups. In summary, TR3-M-NP shows great potential as a tumor-responsive immunotherapy agent with reduced toxicities. STATEMENT OF SIGNIFICANCE: In this study, we developed a bioactive peptide-based checkpoint inhibitor that is active only in tumors and not in normal tissues, thereby potentially avoiding immune-related adverse effects. We discovered a short anti-PD-L1 peptide, TR3, that blocks the PD-1/PD-L1 interaction. We chemically modified the TR3 peptide to self-assemble into a micelle-like nanoparticle (TR3-M-NP), which itself cannot block the PD-1/PD-L1 interaction but releases the active TR3 peptide in tumors upon cleavage by MMP-2. In contrast, the nanoparticle is randomly degraded in normal tissues into peptides fragments that cannot block the PD-1/PD-L1 interaction. Upon intraperitoneal injection, TR3-M-NP5k was activated specifically in tumors through enzyme cleavage, leading to the inhibition of tumor growth and extended survival compared to the control groups. In summary, TR3-M-NP holds significant promise as a tumor-responsive immunotherapy agent with reduced toxicities. The bioactive platform has the potential to be used for other types of checkpoint inhibitor.

Soluble vector family member 6 (SLC2A6) has been implicated in the aggressiveness and poor prognosis of various cancers, yet its specific role in hepatocellular carcinoma (HCC) remains to be fully elucidated. This study utilized multiple databases to investigate the relationship between SLC2A6 expression and clinical stage, methylation status, drug sensitivity, immune infiltration, and immune checkpoint regulation. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted. Furthermore, in vitro and in vivo experiments were performed to assess the impact of SLC2A6 knockout on the proliferation, migration, invasion, and underlying mechanisms in hepatocellular carcinoma (LIHC) cells. SLC2A6 expression was significantly correlated with tumor prognosis, clinical stage, and methylation levels, and was found to influence immune cell infiltration and immune checkpoint gene expression. In LIHC, SLC2A6 was associated with key biological processes, including the cell cycle, P53 signaling, and ferroptosis. Knockdown of SLC2A6 markedly suppressed the proliferation, migration, and invasion of HCC cells, with this inhibition being closely tied to the ferroptosis pathway. SLC2A6 plays a pivotal role in the regulation of pan-cancer processes, particularly in tumor prognosis and immune-related mechanisms. In LIHC, it emerges as a potential prognostic biomarker and therapeutic target for the regulation of ferroptosis, offering new insights for targeted cancer therapies.

A hypoxic metabolism environment in the tumors is often associated with poor prognostic events such as tumor progression and treatment resistance. In gastric cancer, the mechanism of how hypoxia metabolism affects the tumor microenvironment and immunotherapy efficacy remains to be elucidated.

We used the bulk-mapping method to analyze the signatures correlated with the response of immunotherapy in the single-cell dataset. Cellular, pathway, and gene were systematically analyzed in both single-cell and bulk validation datasets.

The most significant cell proportion difference between the response and non-response groups was in endothelial cells, which represent the malignant cells. VWF was specifically overexpressed in endothelial cells and was the hub gene of differential genes. EPAS1 was a VWF trans-regulated gene and highly positively correlated with VWF in expression. Knockdown experiments demonstrated that siVWF reduced the expression of VWF, EPAS1, and HIF1A, as well as the synthesis of lactate and adenosine which are indicators of hypoxic metabolism. These results suggest that the overexpression of core malign endothelial genes such as VWF drives hypoxic metabolism in tumors and creates an immunosuppressive environment that reduces the efficacy of immunotherapy. The adverse prognosis of the hypoxia signature was validated in the bulk cohort and significance was further enhanced after selecting core genes and combined survival weight scoring.

In summary, high expression of the malignant endothelial cell driver genes VWF and EPAS1 enhances hypoxic metabolism, and malignant cell-immune cell interactions suppress the immune response. Therefore, the two core genes of hypoxic metabolism might represent potential therapeutic and predicting biomarkers for immunotherapy of gastric cancer in the future.

Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.

Immunotherapy, especially immune checkpoint inhibitor (ICI) therapy, has yielded remarkable outcomes for some patients with solid cancers, but others do not respond to these treatments. Recent research has identified the gut microbiota as a key modulator of immune responses, suggesting that its composition is closely linked to responses to ICI therapy in cancer treatment. As a result, the gut microbiome is gaining attention as a potential biomarker for predicting individual responses to ICI therapy and as a target for enhancing treatment efficacy. In this review, we discuss key findings from human observational studies assessing the effect of antibiotic use prior to ICI therapy on outcomes and identifying specific gut bacteria associated with favorable and unfavorable responses. Moreover, we review studies investigating the possibility of patient outcome prediction using machine learning models based on gut microbiome data before starting ICI therapy and clinical trials exploring whether gut microbiota modulation, for example via fecal microbiota transplantation or live biotherapeutic products, can improve results of ICI therapy in patients with cancer. We also briefly discuss the mechanisms through which the gut microbial-derived products influence immunotherapy effectiveness. Further research is necessary to fully understand the complex interactions between the host, gut microbiota, and immunotherapy and to develop personalized strategies that optimize responses to ICI therapy.

Radiopharmaceuticals involve the local delivery of radionuclides to targeted lesions for the diagnosis and treatment of multiple diseases. Radiopharmaceutical therapy, which directly causes systematic and irreparable damage to targeted cells, has attracted increasing attention in the treatment of refractory diseases that are not sensitive to current therapies. As the Food and Drug Administration (FDA) approvals of [177Lu]Lu-DOTA-TATE, [177Lu]Lu-PSMA-617 and their complementary diagnostic agents, namely, [68Ga]Ga-DOTA-TATE and [68Ga]Ga-PSMA-11, targeted radiopharmaceutical-based theranostics (radiotheranostics) are being increasingly implemented in clinical practice in oncology, which lead to a new era of radiopharmaceuticals. The new generation of radiopharmaceuticals utilizes a targeting vector to achieve the accurate delivery of radionuclides to lesions and avoid off-target deposition, making it possible to improve the efficiency and biosafety of tumour diagnosis and therapy. Numerous studies have focused on developing novel radiopharmaceuticals targeting a broader range of disease targets, demonstrating remarkable in vivo performance. These include high tumor uptake, prolonged retention time, and favorable pharmacokinetic properties that align with clinical standards. While radiotheranostics have been widely applied in tumor diagnosis and therapy, their applications are now expanding to neurodegenerative diseases, cardiovascular diseases, and inflammation. Furthermore, radiotheranostic-empowered precision medicine is revolutionizing the cancer treatment paradigm. Diagnostic radiopharmaceuticals play a pivotal role in patient stratification and treatment planning, leading to improved therapeutic outcomes in targeted radionuclide therapy. This review offers a comprehensive overview of the evolution of radiopharmaceuticals, including both FDA-approved and clinically investigated agents, and explores the mechanisms of cell death induced by radiopharmaceuticals. It emphasizes the significance and future prospects of theranostic-based radiopharmaceuticals in advancing precision medicine.

Cancer has long been a significant threat to human life and health. The advent of immune checkpoint blockade strategies has reversed cancer-induced immune suppression, advanced the development of immunotherapy, and offered new hope in the fight against cancer. Aptamers, which possess the same specificity and affinity as antibodies, are advantageous due to their synthetic accessibility and ease of modification, providing novel insights for immune checkpoint research. In this review, we outline the key aptamers currently developed for immune checkpoints such as CTLA-4, PD-1, PD-L1 and Siglec-15. We explore their potential in therapeutic strategies, including functionalizing or engineering aptamers for covalent binding, valency control, and nanostructure assembly, as well as investigating molecular mechanisms such as glycosylated protein functions and cell-cell interactions. Finally, the future applications of aptamers in immunotherapy are discussed.

Advancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders.

CAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti-N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies.

CAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.