Apoptosis is vital for improving the efficacy of lung cancer (LC) immunotherapy by targeting cancer cell elimination. Despite its importance, there is a lack of comprehensive bibliometric studies analyzing global research on apoptosis in LC immunotherapy. This analysis aims to address this gap by highlighting key trends, contributors, and future directions. A total of 969 publications from 1996 to 2024 were extracted from the Web of Science Core Collection. Analysis was conducted using VOSviewer, CiteSpace, and the R package 'bibliometrix.' The study included contributions from 6,894 researchers across 1,469 institutions in 61 countries, with research published in 356 journals. The volume of publications has steadily increased, led by China and the United States, with Sichuan University as the top contributor. The journal Cancers published the most articles, while Cancer Research had the highest co-citations. Yu-Quan Wei was the leading author, and Jemal, A. was the most frequently co-cited. Key research themes include "cell death mechanisms," "immune regulation," "combination therapies," "gene and nanomedicine applications," and "traditional Chinese medicine (TCM)." Future research is likely to focus on "coordinated regulation of multiple cell death pathways," "modulation of the tumor immune microenvironment," "optimization of combination therapies," "novel strategies in gene regulation," and the "integration of TCM" for personalized treatment. This is the first bibliometric analysis on the role of apoptosis in LC immunotherapy, providing an landscape of global research patterns and emerging therapeutic strategies. The findings offer insights to guide future research and optimize treatment approaches.

In order to take advantage of both immunotherapeutic and epigenetic antitumor agents, a series of imidazothiazole-based hydroxamic acid derivatives were designed based on the pharmacophore fusion strategy and evaluated as potent IDO1 and HDAC6 dual inhibitors. Among these inhibitors, the most potent compound 3-(4-Bromophenyl)-N-{4-[(7-(hydroxyamino)-7-oxoheptyl)amino]phenyl}imidazo[2,1-b]thiazole-5-carboxamide (10e) showed considerable IDO1 inhibitory activity and a good selectivity profile for HDAC6 over the other HDAC isoforms. The intracellular inhibition of HDAC6 by 10e was validated by Western blot analysis. Docking studies illustrated that the possible binding modes of compound 10e interacted with IDO1 and HDAC6. Moreover, compound 10e was found to arrest the cell cycle at the G2/M phase in HCT-116 cells. In particular, compound 10e also exhibited potent in vivo antitumor efficacy in CT26 tumor-bearing BALB/c mice models, with no significant toxicity. Collectively, this work provides a promising lead compound that serves as IDO1/HDAC6 dual inhibitor for the development of novel antitumor agents.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, and immunotherapy has demonstrated significant therapeutic benefit in HCC. Indole-3-carbinol (I3C), a naturally occurring ingredient of cruciferous vegetables, significantly inhibits the growth of a wide range of tumors. However, its mechanism of action has not been fully elucidated.

This study aims to verify and explore the immunomodulatory effect of I3C in HCC models, and to investigate the specific role and mechanism by which I3C affects PD-L1 expression through the ubiquitination of NF-κB p105.

In vitro, I3C was treated with HepG2 cells and relevant indicators were analyzed. In vivo, the mouse HCC model was established and the effect of I3C on tumors and immune function was evaluated. Subsequently, the downstream target of I3C was found through target prediction, molecular docking, and molecular dynamics simulation. Finally, combined therapy was used to further investigate the effect of I3C on mouse HCC tumors.

We observed that I3C resulted in decreased programmed cell death ligand 1 (PD-L1) expression in HepG2 cells and increased CD8 T cell infiltration in tissues. Subsequently, target prediction and molecular docking demonstrated that I3C was able to efficiently bind to NF-κB p105. In addition, overexpression of NF-κB p105 upregulated PD-L1 expression and almost completely eliminated the inhibitory effect of I3C. Notably, the combination of I3C and PD-L1 monoclonal antibodies showed synergistic anti-tumor effects in the mouse HCC model.

This study demonstrated that I3C inhibits PD-L1-mediated immune evasion in HCC via suppressing NF-κB p105 ubiquitination. The role of I3C in tumors deserves further investigation and provides the foundation for the future development of novel immunotherapeutic drugs.

Islet β-cell dedifferentiation is a major pathological mechanism of type 2 diabetes (T2D). Forkhead box o1 (Foxo1) is a master regulator of β-cell dedifferentiation. The mechanisms by which Foxo1 expression is regulated remain unexplored. Epigenetic modification is involved in the occurrence and development of T2D. Ubiquitin-like with PDH and ring finger domains 1 (Uhrf1), as an important epigenetic regulator, is associated with the maintenance of DNA methylation and histone modification.

This study aimed to discover whether Uhrf1 regulates Foxo1 expression and β-cell dedifferentiation of rat insulinoma (INS-1) cells.

RT-qPCR and Western blot were performed to detect the levels of Uhrf1, Foxo1, β-cell dedifferentiation, and proliferation and apoptosis related indicators. ChIP-qPCR was used to analyze the relative lysine trimethylation at positions 4, 9, and 27 on histone H3 (H3K4/9/27me3) enrichment on the Foxo1 promoter. Dual-luciferase reporter assay was performed to assess the interaction between Uhrf1 and Foxo1. Finally, a diabetic rat model was established and the rat islet β-cells were isolated.

Glucolipotoxicity-induced β-cell dedifferentiation of INS-1 cells, which was restored after Uhrf1 overexpression. Mechanistically, Uhrf1 regulated the H3K4/9/27me3 of the Foxo1 promoter region. Besides, Foxo1 overexpression suppressed β-cell dedifferentiation of INS-1 cells. Moreover, islet β-cells isolated from diabetic model rats showed increased dedifferentiation.

Uhrf1 knockdown promoted H3K27me3 and H3K9me3 and reduced H3K4me3 level in INS-1 cells, resulting in the downregulation of Foxo1 expression, thus promoting β-cell dedifferentiation.

Bladder cancer (BC) is a fatal malignancy of the urinary tract with limited effective biomarkers and therapeutic targets. This paper delved into the mechanism of MYH11 and DNMT1 in BC progression.

Differential genes obtained from the GSE3167 dataset were analyzed by the R language limma package. RT-qPCR, Western blot, and immunohistochemistry were carried out to assess MYH11 and DNMT1 expression in BC cell lines and BC tissues. Cell migration, invasion, proliferation, and apoptosis were detected by Transwell assay, CCK-8, and TUNEL after different lentiviral vector treatments. MB49 cells with different infections were administered into mice to monitor tumor growth and immune escape. Flow cytometry detected the rate of CD45+CD4+-positive cells in the tumor tissues and PD-1 and TIM-3 expression in CD4+ T cells. MYH11 methylation was analyzed using the qMSP assay. ChIP and dual-luciferase assay were used for regulatory assays.

MYH11 was lowly expressed in BC. Overexpression of MYH11 inhibited the malignant progression of BC cells, promoted anti-tumor immune responses of CD4+ T cells, and inhibited immune escape and tumor development in mice. DNMT1 inhibited MYH11 expression by elevating MYH11 promoter methylation. DNMT1 inhibition impeded the immune escape of BC cells, which was reversed by silencing MYH11. DNMT1 silencing prevented immune escape via transcriptional activation of MYH11 and hindered tumor growth in mice.

DNMT1 promotes immune escape and malignant progression of BC by methylating the promoter of MYH11.

Enhancer of zeste homolog 2 (EZH2) is highly expressed in triple-negative breast cancer (TNBC) and induces massive histone modification via trimethylation at lysine 27 of histone H3 (H3K27me3). The expression level of programmed death ligand 1 (PD-L1) is crucial for determining the indications for immune checkpoint inhibitors in patients with TNBC. This study aimed to clarify the regulatory roles of EZH2 and H3K27me3 in the PD-L1 expression in TNBC cells.

The change in the expression of PD-L1 at mRNA and protein levels was investigated by establishing an EZH2-knockdown MDA-MB-231 cell line using siRNA followed by RT-qPCR and western blotting analyses. Localization of the PD-L1 protein was assessed using immunofluorescence. Chromatin immunoprecipitation (ChIP) assays were performed to investigate the histone methylation status of PD-L1 promoter regions. The correlation among PD-L1, EZH2, and H3K27me3 protein expressions was explored in 57 patients with TNBC through immunohistochemistry.

Knockdown of EZH2 restored the PD-L1 expression and localization of PD-L1 protein in the cellular membrane. ChIP assay revealed that the knockdown of EZH2 diminished H3K27 trimethylation and enhanced H3K4 trimethylation in the promoter region of PD-L1. Immunohistochemical analysis of TNBC specimens reflected an inverse correlation between PD-L1 expression and H3K27me3 nuclear positivity; however, no correlation between H3K27me3 status and EZH2 expression was observed.

The downregulation of EZH2 can potentially enhance the efficacy of immune checkpoint inhibitors in patients with TNBC and may provide a new therapeutic strategy.

Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME's complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.

Despite harboring the highest tumor mutational burden of all cancers, basal cell carcinoma (BCC) has low immunogenicity. Here, we demonstrate that BCC's low immunogenicity is associated with epigenomic suppression of antigen presentation machinery reminiscent of its cell of origin. Primary BCC had low T cell infiltrates and low human leukocyte antigen class I (HLA-I) expression compared with cutaneous squamous cell carcinoma (SCC) and normal keratinocytes. Forkhead box C1 (Foxc1), a regulator of quiescence in hair follicle stem cells, was expressed in BCC. Foxc1 bound to promoter of interferon regulatory factor 1 and HLA-I genes, leading to their deacetylation and reduced expression. A histone deacetylase inhibitor, entinostat, overcame Foxc1's effect and upregulated HLA-I in BCC. Topical entinostat plus imiquimod immunotherapy blocked BCC development in mice. Collectively, our findings demonstrate that low BCC immunogenicity is associated with a stem-like quiescent program preserved in the tumor cells, which can be blocked to enable BCC immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been successfully utilized in patients with non-small cell lung cancer (NSCLC), EGFR-mutated patients didn't benefit from ICIs. The underlying mechanisms for the poor efficacy of this subgroup remain unclear.

CD8+T cells cytotoxicity, DCs phagocytosis and immunofluorescence assay were applied to examine the immunosuppressive microenvironment of NSCLC. m6A RNA immunoprecipitation, luciferase assay and immunohistochemistry were used to explore the relationship between CD47 and ALKBH5 in EGFR-TKI resistant NSCLC. Autochthonous EGFR-driven lung tumor mouse model and PDXs were performed to explore the therapeutic potential of CD47 antibody and EGFR-TKI combination.

We found that EGFR-TKI resistance promoted a more immunosuppressive tumor microenvironment and inhibited anti-tumor functions of CD8+ T cells. Mechanistically, the m6A eraser ALKBH5 was inhibited in EGFR-TKI resistant NSCLC, which subsequently upregulates CD47 by catalyzing m6A demethylation and causes immunosuppression. Combined treatment with EGFR-TKI and inhibitors of CD47 enhances antitumor immunity and EGFR-TKI efficacy in vivo.

Collectively, our findings reveal the possible underlying mechanism for poor immune response of ICIs in EGFR-TKI resistant NSCLC and provide preclinical evidence that targeted therapy combined with innate immune checkpoint blockade may provide synergistic effects in NSCLC treatment.

Immunotherapy, particularly immune checkpoint inhibitor therapy, has demonstrated clinical benefits in solid tumours. Despite its satisfactory clinical efficacy, it still faces several issues, such as limited eligibility, low response rates and cytotoxicity. Cancer epigenetics implies that tumour cells exhibit unique phenotypes because of their unique characteristics, thus reprogramming of the epigenome holds promise for cancer therapy. Epigenetic regulation plays an important role in regulating gene expression during tumour development and maintenance. Epigenetic regulators induce cancer cell cycle arrest, apoptosis and differentiation of cancer cells, thereby exerting anti-tumour effects. Recent studies have revealed a significant correlation between epigenetic regulatory factors and immune checkpoint therapy. Epigenetics can modulate various aspects of the tumour immune microenvironment and immune response to enhance the sensitivity of immunotherapy, such as lowering the concentration required and mitigating cytotoxicity. This review primarily discusses DNA methyltransferase inhibitors, histone deacetylase inhibitors, enhancer of zeste homolog 2 inhibitors and lysine-specific demethylase 1 inhibitors, which are associated with transcriptional repression. This repression alters the expression of genes involved in the immune checkpoint, thereby enhancing the effectiveness of immunotherapy. We also discuss the potential and challenges of tumour immunotherapy and highlight its advantages, application challenges and clinical research on integrating epigenetic regulatory factors with tumour immunotherapy.

Targeting the dysregulation of epigenetic mechanisms in cancer has emerged as a promising therapeutic strategy. Although the significant rationale progress of epigenetic therapies in blocking cancer cells, how epigenetic regulation shapes tumor microenvironment (TME) and establishes antitumor immunity remains less understood. Recent study focus has been put on the epigenetic-mediated changes in the fate of immune cells, including the differentiation, expansion, recruitment, functionalization, and exhaustion of T cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), and B cells within the TME. Here, we review the latest molecular and clinical insights into how DNA modifications, histone modification, and epitranscriptome-related regulations shape immune cells of various cancers. We also discuss opportunities for leveraging epigenetic therapies to improve cancer immunotherapies. This review provides the epigenetic foundations of cancer immunity and proposes the future direction of combination therapies.

Recent developments in biomimetic nanoparticles, specifically carbohydrate polymer-coated cell membrane nanoparticles, have demonstrated considerable promise in treating cancer. These systems improve drug delivery by imitating natural cell actions, enhancing biocompatibility, and decreasing immune clearance. Conventional drug delivery methods frequently face challenges with non-specific dispersal and immune detection, which can hinder their efficiency and safety. These biomimetic nanoparticles improve target specificity, retention times, and therapeutic efficiency by using biological components like chitosan, hyaluronic acid, and alginate. Chitosan-based nanoparticles, which come from polysaccharides found in nature, have self-assembly abilities that make them better drug carriers. Hyaluronic acid helps target tissues more effectively, especially in cancer environments where there are high levels of hyaluronic acid receptors. Alginate-based systems also enhance drug delivery by being biocompatible and degradable, making them ideal choices for advanced therapeutic uses. Moreover, these particles hold potential for overcoming resistance to multiple drugs and boosting the body's immune reaction to tumors through precise delivery and decreased side effects of chemotherapy drugs. This review delves into the possibilities of using carbohydrate polymer-functionalized nanoparticles and their impact on enhancing the efficacy of cancer treatment.

The transporter associated with antigen processing (TAP) is a key component of the classical HLA I antigen presentation pathway. Our previous studies have demonstrated that the downregulation of TAP1 contributes to tumor progression and is associated with an increased presence of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. However, it remains unclear whether the elevation of MDSCs leads to immune cell exhaustion in tumors lacking TAP1. In this study, we established mouse models of tumors with TAP1 deficiency, and we employed PMN-MDSC depletion to investigate their impact on the immune microenvironment within the tumors. We found that MDSC depletion significantly altered the immune-suppressive effects of TAP1-deficient tumor when anti-PD-1 treatment was administered. Targeting PMN-MDSC may be a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment.

Immunohistochemistry (IHC) was conducted to assess TAP1 expression in mouse melanoma tissues. Ly6G, F4/80, and NKp46 markers were detected in B16 parental and TAP1 knockout tissues, respectively. To enhance anti-tumor immunity, hyperthermia-treated B16F10 WT cell suspension was injected prior to tumor cell introduction. Subsequently, we established B16F10 TAP1 knockout and WT melanoma mouse models. Tumors were collected, and the immune microenvironment was monitored accordingly. Anti-Ly6G antibody was administered to deplete polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Finally, flow cytometry analysis for immune infiltration, quantitative PCR for cytokine levels, and immunofluorescence assays were performed to analyze the immune response.

The level of Ly6G+ cell infiltration was significantly higher in samples exhibiting low TAP1 expression, while no differences were observed in the infiltration of F4/80+ cells or NKp46+ cells. Furthermore, the immune-suppressive effects associated with PMN-MDSCs were reversed following their elimination; this resulted in an increase in CD8+ T cells and a higher ratio of CD8+ T cells to Tregs, while the infiltration of innate immune cells remained unaffected. Functional markers of these immune cells indicated an active anti-tumoral immune response following the removal of PMN-MDSCs. Quantitative PCR analysis indicated elevated levels of TNF-α and IL-6, accompanied by decreased levels of TGF-β in the tumor microenvironment of TAP1.

Our data indicate that myeloid-derived suppressor cells (PMN-MDSCs) play an essential role in creating a tumorigenic immune microenvironment in TAP1 knockout tumors. Therefore, targeting PMN-MDSCs may become a promising therapeutic strategy for the treatment of tumors with TAP1 deficiency during ICB treatment.

Immunotherapy represents a promising therapeutic strategy for cancer treatment, but its clinical applications are currently hindered by insufficient therapeutic potency, nonspecific delivery, and adverse side effects. Herein, a novel near-infrared II (NIR-II) photo-triggered plasmonic hyperthermia immunomodulator (RP@IR-pcNS@HA nanoparticles (NPs)) for anticancer treatment of both primary and distant cancers is reported. This immunomodulator comprises an IR-1061 dye-encoded NIR-II porous cubic AuAg nanoshell (pcNS) loaded with a Toll-like receptor 7 agonist - R837 in phase change materials (PCMs), further modified with hyaluronic acid (HA). In response to NIR-II photoirradiation, the RP@IR-pcNS@HA NPs controllably deliver and release R837 to tumor sites, subsequently perform plasmonic hyperthermia therapy for direct ablation of primary tumors, and elicit robust anticancer immune responses. It is demonstrated that upon NIR-II irradiation, such a plasmonic hyperthermia immunomodulator combined with anti-programmed death 1 antibody (αPD-1) completely eradicates both primary and distant cancers. In addition, this combination treatment successfully elicits robust immune memory responses for effective suppression of recurrence and distant metastasis of cancer. With the excellent NIR-II surface-enhanced Raman scattering (SERS) detection ability, the RP@IR-pcNS@HA NPs combined with αPD-1 represent an efficient way to develop high-performance theranostic agents for SERS-guided combination cancer photoimmunotherapy.

Curzerenone is a major component of the traditional herbal medicine Curcumae Rhizoma with potential cancer-suppressing effects. This study aims to investigate the treatment effect of Curzerenone on cervical cancer cells and the underpinning mechanism. HeLa and SiHa cells were treated with Curzerenone. The 100 μM Curzerenone treatment repressed proliferation, migration, and invasion of the cells. The Curzerenone treatment also reduced cellular expression of programmed death ligand 1, which increased the proliferation and activity of CD8+ T cells in a co-culture system with cancer cells. Casein kinase 2 beta (CSNK2B), a predicted physiological target of Curzerenone, was found to be suppressed by Curzerenone. Further overexpression of CSNK2B blocked the treatment effects of Curzerenone. Curzerenone inhibited while CSNK2B triggered activation of the nuclear factor-kappa B (NF-κB) pathway. The oncogenic and immunosuppressive effects of CSNK2B were blocked by an NF-κB-specific inhibitor. In vivo, Curzerenone treatment inhibited the tumorigenic activity of cancer cells, and it increased the proportion of CD8+ T cells in the xenograft tumor tissues. However, these anti-tumor effects were diminished by the CSNK2B overexpression as well. In conclusion, this research suggests that Curzerenone targets CSNK2B and inactivates the NF-κB signaling to suppress malignancy and immune evasion in cervical cancer.

Histone deacetylase (HDAC) inhibitors have been reported to exhibit immunomodulatory activities, including the upregulation of major histocompatibility complex class I (MHC class I). Although the immunoproteasome plays a pivotal role in MHC class I antigen presentation, its effect on immunotherapy for clear cell renal cell carcinoma (ccRCC) remains unclear.

This study assessed whether OBP-801, a novel HDAC inhibitor, affects the expression of immunoproteasome subunits and subsequently the MHC class-I-mediated anti-cancer immunity in ccRCC. We analyzed the data of 531 patients with ccRCC from the Cancer Genome Atlas Kidney Clear Cell Carcinoma database. We further evaluated the treatment efficacy of the combination of OBP-801 and anti-PD-1 in a ccRCC mouse model.

Low molecular mass polypeptide (LMP) 2 was correlated most positively with CD3E, CD8A, and CD8B expression and estimated CD8+ T cell number. In vitro studies showed that OBP-801 upregulated MHC class I presentation by inducing LMP2 expression in the ccRCC cell lines RENCA, 786-O, and Caki-1. In vivo studies in a syngeneic mouse model with subcutaneous implantation of RENCA cells showed that OBP-801 treatment increased the percentage of CD45+CD3e+ T cells in tumor-infiltrating lymphocytes. The combination of anti-PD-1 antibody and OBP-801 enhanced the anti-tumor effect, LMP2 protein expression, and MHC class I presentation in tumor cells. MHC class I presentation in the tumors of each mouse was positively correlated with the percentage of CD45+CD3e+ T cells.

Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC.

Immune checkpoint blockade therapy has revolutionized cancer treatment, but resistance remains prevalent, often due to dysfunctional tumor-infiltrating lymphocytes. A key contributor to this dysfunction is mitochondrial dysfunction, characterized by defective oxidative phosphorylation, impaired adaptation, and depolarization, which promotes T cell exhaustion and severely compromises antitumor efficacy. This review summarizes recent advances in restoring the function of exhausted T cells through mitochondria-targeted strategies, such as metabolic remodeling, enhanced biogenesis, and regulation of antioxidant and reactive oxygen species, with the aim of reversing the state of T cell exhaustion and improving the response to immunotherapy. A deeper understanding of the role of mitochondria in T cell exhaustion lays the foundation for the development of novel mitochondria-targeted therapies and opens a new chapter in cancer immunotherapy.

Histones are essential nuclear proteins that package eukaryotic DNA into chromosomes, play a vital role in gene regulation, DNA replication, DNA repair and chromosome condensation. Understanding histone modifications is crucial for grasping biological and disease-related processes. Specific alterations in histone modifications serve as sensitive and selective biomarkers for conditions like cancer, impacting both tumor and immune cells and affecting their interactions. Indeed, the interest in histone modifications is growing in the field of tumor immunology and immunotherapy. Different techniques have been developed to characterize histone proteins and their modifications. Here, we present a simple acid extraction protocol to identify and quantify histones. The workflow described here can be used to detect and measure histone proteins or specific residues of histone, even capturing changes resulting from treatment with epigenetic drugs (Epi-drugs) or other drugs in in different human cancer cell line models.

Isobutyric acid (IBA), a short-chain fatty acid, has been unequivocally demonstrated to exert significant influence on the progression of colorectal cancer (CRC). Nevertheless, a comprehensive understanding of its intricate regulatory mechanisms remains elusive.

Employing advanced techniques such as western blot, RT-qPCR, and flow cytometry, we systematically investigated the impact of IBA on the expression of PD-L1 in CRC cells. Concurrently, employing RNA silencing technology and small-molecule inhibitors, we delved into the molecular intricacies underlying the regulatory axis of IBA involving ROCK1/c-Myc/PD-L1. Furthermore, through flow cytometry analysis, we examined the alterations in the tumor immune microenvironment following anti-PD-L1 antibody therapy in a murine tumor model treated with IBA.

Elevated levels of IBA were found to robustly activate PD-L1 expression in CRC cells both in vitro and in vivo, concomitantly reshaping the tumor immune microenvironment. Subsequent mechanistic investigations unveiled that IBA, through its interaction and activation of ROCK1, promotes the activation of c-Myc, thereby enhancing the transcription of PD-L1. Silencing of ROCK1 and application of ROCK1 inhibitors effectively reversed the regulatory effects of IBA on PD-L1. Additionally, IBA inhibited the activity of infiltrating CD8+ T cells, resulting in diminished antitumor immunity and attenuating the sensitivity to anti-PD-L1 therapy.

Our study elucidates a novel mechanism by which IBA inhibits the sensitivity of CRC to anti-PD-L1 antibody therapy. Emphasizing IBA and its downstream pathways as potential therapeutic targets for immune therapy resistance mechanisms, our findings provide a novel theoretical foundation for overcoming immune therapy resistance.

Immune checkpoint inhibitors (ICIs) offer promise in breaking through the treatment and survival dilemma of triple-negative breast cancer (TNBC), yet only immunomodulatory subtype and ≈5% TNBC patients respond as monotherapy due to lack of effector immune cells (internal problem) and physical barrier (external limitation) formed by cancer-associated fibroblasts (CAFs). A hydrogel drug-delivery platform, ALG@TBP-2/Pt(0)/nintedanib (ALG@TPN), is designed to induce strong immune functions and the dual elimination of the internal and external tumor microenvironment (TME). Activated by white light, through type I and II photodynamic therapy (PDT), TBP-2 generates large amounts of reactive oxygen species (ROS) intracellularly, oxidizing mitochondrial DNA (mtDNA). The unique catalase activity of Pt(0) converts endogenous H2O2 to O2, reducing the anoxia-limiting PDT and enhancing ROS generation efficacy. Abundant ROS can oxidize Pt(0) to cytotoxic Pt(II), damaging the nuclear DNA (nDNA). Dual damage to mtDNA and nDNA might bi-directionally activate the cGAS/STING pathway and enhance the immune cell response. Besides, nintedanib demonstrates a significant inhibitory effect on CAFs, weakening the immune barrier and deepening immune cell infiltration. Overall, the study provides a self-oxygenating hydrogel with the "PDT/chemotherapy/anti-CAFs" effect, triggering the cGAS/STING pathway to reshape the TME. Both internal and external interventions increase anti-TNBC immune responses.

Leukemia remains a major therapeutic challenge in clinical oncology. Despite significant advancements in treatment modalities, leukemia remains a significant cause of morbidity and mortality worldwide, as the current conventional therapies are accompanied by life-limiting adverse effects and a high risk of disease relapse. Histone deacetylase inhibitors have emerged as a promising group of antineoplastic agents due to their ability to modulate gene expression epigenetically. In this review, we explore these agents, their mechanisms of action, pharmacokinetics, safety and clinical efficacy, monotherapy and combination therapy strategies, and clinical challenges associated with histone deacetylase inhibitors in leukemia treatment, along with the latest evidence and ongoing studies in the field. In addition, we discuss future directions to optimize the therapeutic potential of these agents.

Immune checkpoint therapy has emerged as an effective treatment option for various types of cancers. Key immune checkpoint molecules, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and lymphocyte activation gene 3 (LAG-3), have become pivotal targets in cancer immunotherapy. Antibodies designed to inhibit these molecules have demonstrated significant clinical efficacy. Nevertheless, the ability to monitor changes in the immune status of tumors and predict treatment response remains limited. Conventional methods, such as assessing lymphocytes in peripheral blood or conducting tumor biopsies, are inadequate for providing real-time, spatial information about T-cell distributions within heterogeneous tumors. Positron emission tomography (PET) using T-cell specific probes represents a promising and noninvasive approach to monitor both systemic and intratumoral immune changes during treatment. This technique holds substantial clinical significance and potential utility. In this paper, we review the applications of PET probes that target immune cells in molecular imaging.

Programmed death receptor-1 (PD-1) and its ligand, programmed death ligand-1 (PD-L1) are essential molecules that are key in modulating immune responses. PD-L1 is constitutively expressed on various immune cells, epithelial cells, and cancer cells, where it functions as a co-stimulatory molecule capable of impairing T-cell mediated immune responses. Upon binding to PD-1 on activated T-cells, the PD-1/PD-L1 interaction triggers signaling pathways that can induce T-cell apoptosis or anergy, thereby facilitating the immune escape of tumors. In urological cancers, including bladder cancer (BCa), renal cell carcinoma (RCC), and prostate cancer (PCa), the upregulation of PD-L1 has been demonstrated. It is linked to poor prognosis and enhanced tumor immune evasion. Recent studies have highlighted the significant role of the PD-1/PD-L1 axis in the immune escape mechanisms of urological cancers. The interaction between PD-L1 and PD-1 on T-cells further contributes to immunosuppression by inhibiting T-cell activation and proliferation. Clinical applications of PD-1/PD-L1 checkpoint inhibitors have shown promising efficacy in treating advanced urological cancers, significantly improving patient outcomes. However, resistance to these therapies, either intrinsic or acquired, remains a significant challenge. This review aims to provide a comprehensive overview of the role of the PD-1/PD-L1 signaling pathway in urological cancers. We summarize the regulatory mechanism underlying PD-1 and PD-L1 expression and activity, including genetic, epigenetic, post-transcriptional, and post-translational modifications. Additionally, we discuss current clinical research on PD-1/PD-L1 inhibitors, their therapeutic potential, and the challenges associated with resistance. Understanding these mechanisms is crucial for developing new strategies to overcome therapeutic limitations and enhance the efficacy of cancer immunotherapy.

Immunotherapies hold immense potential for achieving durable potency and long-term survival opportunities in cancer therapy. As vital biological mediators, peptides with high tissue penetration and superior selectivity offer significant promise for enhancing cancer immunotherapies (CITs). However, physicochemical peptide features such as conformation and stability pose challenges to their on-target efficacy. This review provides a comprehensive overview of recent advancements in therapeutic peptides targeting key steps of the cancer-immunity cycle (CIC), including tumor antigen presentation, immune cell regulation, and immune checkpoint signaling. Particular attention is given to the opportunities and challenges associated with these peptides in boosting CIC within the context of clinical progress. Furthermore, possible future developments in this field are also discussed to provide insights into emerging CITs with robust efficacy and safety profiles.

Biliary tract cancers (BTCs) have rising incidence and mortality rates. Chemotherapy's limited efficacy has led to exploring new treatments like immunotherapy. which offers modest benefits. Moreover, the identification of reliable predictive biomarkers for immune checkpoint therapy in BTCs remains elusive, hindering personalized treatment strategies. This review provides an overview of the current landscape of emerging biomarkers for immunotherapy response in BTCs. We discuss the incremental benefits of combination therapy and the evolving role of immunotherapy in managing advanced BTC. Additionally, we highlight the need for robust predictive biomarkers to optimize treatment outcomes and foster a more individualized approach to patient care. We aim to identify promising research avenues and strategies to enhance therapeutic efficacy and patient survival in BTCs.

Although immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody, and anti-CTLA-4 antibody) have displayed considerable success in the treatment of malignant tumors, the therapeutic effect is still unsatisfactory for a portion of patients. Therefore, it is imperative to develop strategies to enhance the effect of these ICIs. Increasing evidence strongly suggests that the key to this issue is to transform the tumor immune microenvironment from a state of no or low immune infiltration to a state of high immune infiltration and enhance the tumor cell-killing effect of T cells. Therefore, some combination strategies have been proposed and this review appraise a summary of 39 strategies aiming at enhancing the effectiveness of ICIs, which comprise combining 10 clinical approaches and 29 foundational research strategies. Moreover, this review improves the comprehensive understanding of combination therapy with ICIs and inspires novel ideas for tumor immunotherapy.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of castration-resistant prostate cancer. It is characterized by low or no expression of the androgen receptor (AR), activation of AR-independent signaling, and increased neuroendocrine phenotype. Most of NEPC is induced by treatment of androgen deprivation therapy and androgen receptor pathway inhibitors (ARPIs). Currently, the treatment of NEPC follows the treatment strategy for small-cell lung cancer, lacking effective drugs and specific treatment options. This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (zeste homolog 2 inhibitors, lysine-specific demethylase 1 inhibitors), aurora kinase A inhibitors, poly-ADP-ribose polymerase inhibitors, delta-like ligand 3 targeted therapies, a combination of immunotherapies, etc. Other promising targets and future directions are also discussed in this review. These novel targets and therapies may provide new opportunities for the treatment of NEPC.

Regulatory T cells (Tregs), characterized by the expression of Forkhead Box P3 (FOXP3), constitute a distinct subset of T cells crucial for immune regulation. Tregs can exert direct and indirect control over immune homeostasis by releasing inhibitory factors or differentiating into Th-like Treg (Th-Treg), thereby actively contributing to the prevention and treatment of autoimmune diseases. The epigenetic regulation of FOXP3, encompassing DNA methylation, histone modifications, and post-translational modifications, governs the development and optimal suppressive function of Tregs. In addition, Tregs can also possess the ability to maintain homeostasis in diverse microenvironments through non-suppressive mechanisms. In this review, we primarily focus on elucidating the epigenetic regulation of Tregs as well as their multifaceted roles within diverse physiological contexts while looking forward to potential strategies involving augmentation or suppression of Tregs activity for disease management, particularly in light of the ongoing global COVID-19 pandemic.

Lysine methylation is a crucial post-translational modification (PTM) that significantly impacts gene expression regulation. This modification not only influences cancer development directly but also has significant implications for the immune system. Lysine methylation modulates immune cell functions and shapes the anti-tumor immune response, highlighting its dual role in both tumor progression and immune regulation. In this review, we provide a comprehensive overview of the intrinsic role of lysine methylation in the activation and function of immune cells, detailing how these modifications affect cellular processes and signaling pathways. We delve into the mechanisms by which lysine methylation contributes to tumor immune evasion, allowing cancer cells to escape immune surveillance and thrive. Furthermore, we discuss the therapeutic potential of targeting lysine methylation in cancer immunotherapy. Emerging strategies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy, are being explored for their efficacy in modulating lysine methylation to enhance anti-tumor immune responses. By targeting these modifications, we can potentially improve the effectiveness of existing treatments and develop novel therapeutic approaches to combat cancer more effectively.

Edible and medicinal herbs1 (EMHs) refer to a class of substances with dual attribution of food and medicine. These substances are traditionally used as food and also listed in many international pharmacopoeias, including the European Pharmacopoeia, the United States Pharmacopoeia, and the Chinese Pharmacopoeia. Some classical formulas that are widely used in traditional Chinese medicine include a series of EMHs, which have been shown to be effective with obvious characteristics and advantages. Notably, these EMHs and Chinese classical prescriptions2 (CCPs) have also attracted attention in international herbal medicine research because of their low toxicity and high efficiency as well as the rich body of experience for their long-term clinical use.

Our purpose is to explore the potential therapeutic effect of EMHs with immune-inflammatory modulation for the study of modern cancer drugs.

In the present study, we present a detailed account of some EMHs used in CCPs that have shown considerable research potential in studies exploring modern drugs with immune-inflammatory modulation.

Approximately 500 publications in the past 30 years were collected from PubMed, Web of Science and ScienceDirect using the keywords, such as natural products, edible and medicinal herbs, Chinese medicine, classical prescription, immune-inflammatory, tumor microenvironment and some related synonyms. The active ingredients instead of herbal extracts or botanical mixtures were focused on and the research conducted over the past decade were discussed emphatically and analyzed comprehensively.

More than ten natural products derived from EMHs used in CCPs are discussed and their immune-inflammatory modulation activities, including enhancing antitumor immunity, regulating inflammatory signaling pathways, lowering the proportion of immunosuppressive cells, inhibiting the secretion of proinflammatory cytokines, immunosuppressive factors, and inflammatory mediators, are summarized.

Our findings demonstrate the immune-inflammatory modulating role of those EMHs used in CCPs and provide new ideas for cancer treatment in clinical settings.

This review explores the emerging role of extracellular vesicles (EVs) in modulating immune system function and their application in novel cancer immunotherapy strategies, with a focus on colorectal cancer (CRC). EVs, as carriers of bioactive molecules, have shown potential in enhancing immune responses and overcoming the limitations of traditional therapies. We discuss the biogenesis, types, and functional roles of immune cell-derived EVs, their interactions with cancer cells, and their implications in antitumor immunity. Challenges such as tumor heterogeneity and immune evasion are addressed, alongside the promising therapeutic prospects of EV-based strategies. This comprehensive analysis underscores the transformative potential of EVs in cancer treatment paradigms.

Targeting the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) pathway has been identified as a successful approach for tumor immunotherapy. Here, we identified that the small molecule 5,7,4'-trimethoxyflavone (TF) from Kaempferia parviflora Wall reduces PD-L1 expression in colorectal cancer cells and enhances the killing of tumor cells by T cells. Mechanistically, TF targets and stabilizes the ubiquitin ligase HMG-CoA reductase degradation protein 1 (HRD1), thereby increasing the ubiquitination of PD-L1 and promoting its degradation through the proteasome pathway. In mouse MC38 xenograft tumors, TF can activate tumor-infiltrating T-cell immunity and reduce the immunosuppressive infiltration of myeloid-derived suppressor cells and regulatory T cells, thus exerting antitumor effects. Moreover, TF synergistically exerts antitumor immunity with CTLA-4 antibody. This study provides new insights into the antitumor mechanism of TF and suggests that it may be a promising small molecule immune checkpoint modulator for cancer therapy.

Immunosuppressive regulatory cells (IRCs) play important roles in negatively regulating immune response, and are mainly divided into myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Large numbers of preclinical and clinical studies have shown that inhibition or reduction of IRCs could effectively elevate antitumor immune responses. However, several studies also reported that excessive inhibition of IRCs function is one of the main reasons causing the side effects of cancer immunotherapy. Therefore, the reasonable regulation of IRCs is crucial for improving the safety and efficiency of cancer immunotherapy. In this review, we summarised the recent research advances in the cancer immunotherapy by regulating the proportion of IRCs, and discussed the roles of IRCs in regulating tumour immune evasion and drug resistance to immunotherapies. Furthermore, we also discussed how to balance the potential opportunities and challenges of using IRCs to improve the safety of cancer immunotherapies.

Nonviral vectors, such as liposomes, offer potential for targeted gene delivery in cancer therapy. Liposomes, composed of phospholipid vesicles, have demonstrated efficacy as nanocarriers for genetic tools, addressing the limitations of off-targeting and degradation commonly associated with traditional gene therapy approaches. Due to their biocompatibility, stability, and tunable physicochemical properties, they offer potential in overcoming the challenges associated with gene therapy, such as low transfection efficiency and poor stability in biological fluids. Despite these advancements, there remains a gap in understanding the optimal utilization of nanoliposomes for enhanced gene delivery in cancer treatment. This review delves into the present state of nanoliposomes as carriers for genetic tools in cancer therapy, sheds light on their potential to safeguard genetic payloads and facilitate cell internalization alongside the evolution of smart nanocarriers for targeted delivery. The challenges linked to their biocompatibility and the factors that restrict their effectiveness in gene delivery are also discussed along with exploring the potential of nanoliposomes in cancer gene therapy strategies by analyzing recent advancements and offering future directions.

Lymphoma is a disease that affects countless lives each year. In order to combat this disease, researchers have been exploring the potential of DNMTi and HDACi drugs. These drugs target the cellular processes that contribute to lymphomagenesis and treatment resistance. Our research evaluated the effectiveness of a combination of two such drugs, hydralazine (DNMTi) and valproate (HDACi), in B-cell and T-cell lymphoma cell lines. Here we show that the combination of hydralazine and valproate decreased the viability of cells over time, leading to the arrest of cell-cycle and apoptosis in both B and T-cells. This combination of drugs proved to be synergistic, with each drug showing significant growth inhibition individually. Microarray analyses of HuT 78 and Raji cells showed that the combination of hydralazine and valproate resulted in the up-regulation of 562 and 850 genes, respectively, while down-regulating 152 and 650 genes. Several proapoptotic and cell cycle-related genes were found to be up-regulated. Notably, three and five of the ten most up-regulated genes in HuT 78 and Raji cells, respectively, were related to immune function. In summary, our study suggests that the combination of hydralazine and valproate is an effective treatment option for both B- and T-lymphomas. These findings are highly encouraging, and we urge further clinical evaluation to validate our research and potentially improve lymphoma treatment.

The lack of an efficient way to screen patients who are responsive to immunotherapy challenges PD1/CTLA4-targeting cancer treatment. Immunotherapeutic efficacy cannot be clearly determined by peripheral blood analyses, tissue gene markers or CT/MR value. Here, we used a radionuclide and imaging techniques to investigate the novel dual targeted antibody cadonilimab (AK104) in PD1/CTLA4-positive cells in vivo.

First, humanized PD1/CTLA4 mice were purchased from Biocytogen Pharmaceuticals (Beijing) Co., Ltd. to express hPD1/CTLA4 in T-cells. Then, mouse colon cancer MC38-hPD-L1 cell xenografts were established in humanized mice. A bispecific antibody targeting PD1/CTLA4 (AK104) was labeled with radio-nuclide iodine isotopes. Immuno-PET/CT imaging was performed using a bispecific monoclonal antibody (mAb) probe 124I-AK104, developed in-house, to locate PD1+/CTLA4+ tumor-infiltrating T cells and monitor their distribution in mice to evaluate the therapeutic effect.

The 124I-AK104 dual-antibody was successfully constructed with ideal radiochemical characteristics, in vitro stability and specificity. The results of immuno-PET showed that 124I-AK104 revealed strong hPD1/CTLA4-positive responses with high specificity in humanized mice. High uptake of 124I-AK104 was observed not only at the tumor site but also in the spleen. Compared with PD1- or CTLA4-targeting mAb imaging, 124I-AK104 imaging had excellent standard uptake values at the tumor site and higher tumor to nontumor (T/NT) ratios.

The results demonstrated the potential of translating 124I-AK104 into a method for screening patients who benefit from immunotherapy and the efficacy, as well as the feasibility, of this method was verified by immuno-PET imaging of humanized mice.

Lymphomas, complex and heterogeneous malignant tumors, originate from the lymphopoietic system. These tumors are notorious for their high recurrence rates and resistance to treatment, which leads to poor prognoses. As ongoing research has shown, epigenetic modifications like DNA methylation, histone modifications, non-coding RNA regulation, and RNA modifications play crucial roles in lymphoma pathogenesis. Epigenetic modification-targeting drugs have exhibited therapeutic efficacy and tolerability in both monotherapy and combination lymphoma therapy. This review discusses pathogenic mechanisms and potential epigenetic therapeutic targets in common lymphomas, offering new avenues for lymphoma diagnosis and treatment. We also discuss the shortcomings of current lymphoma treatments, while suggesting potential areas for future research, in order to improve the prediction and prognosis of lymphoma.