Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment.

BACKGROUND: Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles IL6ST-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. However, the molecular programs mediated by IL6ST/STAT3 in prostate cancer are poorly understood. METHODS: To investigate the role of IL6ST signaling, we constitutively activated IL6ST signaling in the prostate epithelium of a Pten-deficient prostate cancer mouse model in vivo and examined IL6ST expression in large cohorts of prostate cancer patients. We complemented these data with in-depth transcriptomic and multiplex histopathological analyses. RESULTS: Genetic cell-autonomous activation of the IL6ST receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of IL6ST signaling mediates senescence via the STAT3/ARF/p53 axis and recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high IL6ST mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. CONCLUSIONS: Our findings demonstrate a context-dependent role of IL6ST/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development by inducing senescence and immune cell attraction. We challenge the prevailing concept of blocking IL6ST/STAT3 signaling as a functional prostate cancer treatment and instead propose cell-autonomous IL6ST activation as a novel therapeutic strategy.

Cytotoxic Evaluation, Molecular Docking, Molecular Dynamics, and ADMET Prediction of Isolupalbigenin Isolated from Erythrina subumbrans (Hassk). Merr. (Fabaceae) Stem Bark: Unveiling Its Anticancer Efficacy.

Introduction: Erythrina subumbrans, a medical plant found in sub-Saharan Africa and the Western Ghats of India, shows promise as a potential source of bioactive compounds to treat cancer. In our ongoing research on folk medical plants, we report the isolation of flavonoid compound from the stem bark of E. subumbrans along with its cytotoxic activity against breast cancer (MCF-7 and T47D), and cervical cancer (HeLa) cell lines. Purpose: This study aimed to isolate secondary metabolite from the stem bark of E. subumbrans and evaluate its cytotoxic activity to support the use of folk medicinal plants as alternative therapy against cancer. Methods: Isolupalbigenin was isolated from the stem bark of E. subumbrans by column chromatography. Cytotoxic activity against breast cancer (MCF-7 and T47D) and cervical cancer (HeLa) cell lines was evaluated using the MTT assay, whereas the in silico study was evaluated using molecular docking and molecular dynamics against estrogen receptor alpha (ERα). Results: The cytotoxic assay showed that isolupalbigenin inhibited the growth of MCF-7 cell with an IC50 of 31.62 µg∙mL-1, while showing no toxicity against normal human cells (Vero cell line). The molecular docking results suggested that isolupalbigenin can bind to ERα with a lower binding affinity than estradiol, whereas the stability of the isolupalbigenin-ERα complex was confirmed by molecular dynamic simulation with a median Root Mean Square Deviation (RMSD) of 2.80 Å. Toxicity prediction suggested that isolupalbigenin was less likely to cause hepatotoxicity or carcinogenicity, whereas pharmacokinetic prediction suggested that isolupalbigenin has high intestinal absorption with medium Caco2 permeability. In addition, isolupalbigenin was predicted to have a medium volume of distribution (Vd). Conclusion: Isolupalbigenin isolated from the stem bark of E. subumbrans with cytotoxic activity supports further development of plants from the genus Erythrina as a medicinal plant for alternative therapy against cancer.

Synthesis of Sulfonamide-Based Schiff Bases as Potent Anticancer Agents: Spectral Analyses, Biological Activity, Molecular Docking, ADME, DFT, and Pharmacophore Modelling Studies.

The current study focuses on the synthesis and characterization of six benzenesulfonamide-based Schiff base derivatives (7-12) with various electron-withdrawing and electron-donating substituents (-F, -CI, -Br, -CH3, and -OCH3) and the assessment of their antiproliferative activities against human lung (A549) and liver (HepG2) cancer cell lines using in vitro and in silico approaches. The structures of the synthesized compounds (7-12) were elucidated by elemental analysis and FT-IR, 1D (1H, 13C, APT, and DEPT-135), and 2D (HMQC and HMBC) NMR spectroscopies. The cytotoxic activities of the targeted compounds were determined at various concentrations against these cancer cell lines for 72 h, using the MTT method. The targeted molecules (7-12) demonstrated remarkable antiproliferative activities, with IC50 values ranging from 6.032-9.533 µM against the A549 cell line and 5.244-9.629 µM against the HepG2 cell line. These compounds showed activities at lower or very similar concentrations to cisplatin against the A549 cell line and at much lower concentrations than cisplatin against the HepG2 cell line. Among them, compounds 10 and 12 were found to be more effective against A549 and HepG2 cells, respectively, than cisplatin. These compounds were analyzed by interacting with the 1BNA, 4HJO, and 4ASD crystal structures in molecular docking studies.

The Good (Tumor Killing) and the Bad (Cardiovascular Complications) of Immunologic Checkpoint Inhibitors.

PURPOSE OF REVIEW: This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment. RECENT FINDINGS: Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.

Chemical Composition, Anti-microbial, and Cytotoxic Activities of Essential Oil from Magnolia bidoupensis Q. N. Vu leaves, an Endemic Species to the Central Highlands of Vietnam.

An analysis was conducted on the essential oil extracted from the leaves of Magnolia bidoupensis utilizing GC-MS, revealing thirty-three constituents that account for 98.9% of the essential oil. The main components included pogostol (22.4%), δ-selinene (16.2%), and α-amorphene (14.7%). Bioassays were then performed to evaluate the oil's biological activity. The essential oil exhibited antimicrobial activity against all tested microorganisms (six bacterial strains and one fungal strain) using the minimum inhibitory concentration (MIC) method. Additional cytotoxicity tests were conducted on KB, HepG2, MCF-7, and A549 cancer cell lines using the MTT method. The essential oil exhibited strong cytotoxic effects on all four cell lines, with IC50 values ranging from 1.37 ± 0.05 µg/mL (KB) to 2.40 ± 0.06 µg/mL (A549).

Cytotoxic Lesions of the Corpus Callosum (CLOCCs) Related to Hypoglycemia: Clinical Insights and Pathogenesis.

We describe the case of an 88-year-old man with cytotoxic lesions of the corpus callosum (CLOCCs) related to hypoglycemia. The patient developed a disturbance of consciousness following excessive alcohol consumption and anorexia. In the emergency room, his blood sugar level was 9 mg/dL, and he was immediately treated with a rapid infusion of glucose. Brain magnetic resonance imaging (MRI) revealed hyperintensity in the corpus callosum and bilateral deep white matter on diffusion-weighted imaging, along with decreased apparent diffusion coefficient values. The following day, these findings were attenuated, and he was diagnosed with CLOCCs. In this report, we discuss clinical insights and the possible pathogenesis of the development of CLOCCs due to hypoglycemia, considering the previous literature.

In Silico and Glioblastoma Cell Line Evaluation of Thioflavin-Derived Zinc Nanoparticles Targeting Beclin Protein.

INTRODUCTION: This study explores the anticancer potential of Thioflavin-derived zinc nanoparticles (Th-ZnNPs) using both in vitro and in silico methods. Thioflavin, known for its specific binding properties, faces challenges such as bioavailability, rapid metabolism, and solubility. To overcome these limitations and enhance therapeutic efficacy, nanotechnology was utilized to synthesize Th-ZnNPs. These nanoparticles (NPs) are designed to improve drug delivery and effectiveness. The Beclin protein, which plays a critical role in regulating autophagy in cancer cells, was identified as a potential target for these NPs. The study aims to evaluate the interaction between Th-ZnNPs and Beclin protein in glioblastoma cell lines and assess the potential of these NPs as novel anticancer agents. METHODS:  Th-ZnNPs were synthesized using advanced nanotechnology techniques to improve the bioavailability and solubility of Thioflavin. To explore their anticancer potential, in silico analyses were performed, including molecular docking studies to evaluate the binding affinity between the ZnNPs and Beclin protein, which is integral to autophagy regulation. This computational approach identified the Beclin protein as a promising target for the ZnNPs. Complementary in vitro assays were then conducted, where glioblastoma cell lines (procured from the National Centre for Cell Science, Pune, India) were treated with ZnNPs to assess their cytotoxic effects. The assays also included mechanistic studies to validate the interaction between ZnNPs and Beclin protein and to understand their influence on autophagy pathways. RESULTS: The synthesis of Th-ZnNPs successfully enhanced their solubility and bioavailability compared to Thioflavin alone. In silico findings showed a strong binding affinity between the Th-ZnNPs and the Beclin protein, suggesting that these NPs may effectively target cancer cells through this interaction. Beclin protein was validated as a relevant target due to its critical role in autophagy regulation. In vitro assays further confirmed the anticancer potential of the Th-ZnNPs, as they exhibited significant cytotoxic effects on glioblastoma cells. Additionally, mechanistic studies revealed that Th-ZnNPs impact Beclin protein and modulate autophagy pathways, supporting their proposed role as effective anticancer agents. CONCLUSIONS: The study highlights the promising anticancer potential of Th-ZnNPs. By overcoming the limitations of Thioflavin through nanotechnology, these NPs show significant therapeutic promise in targeting glioblastoma cells. The strong binding affinity between Th-ZnNPs and the Beclin protein, coupled with confirmed cytotoxic effects, underscores their potential as novel anticancer agents. This integrated approach not only enhances the delivery and efficacy of Thioflavin but also opens new avenues for targeted therapy in glioblastoma treatment.

Anticancer and bioactivity effect of the AraA-IL13 fusion protein on the glioblastoma cell line.

Background and purpose: Glioblastoma (GBM) is an aggressive and malignant brain cancer with the highest mortality and low survival rates. To discover a more specific and efficient treatment for GBM, we synthesized and examined the cytotoxic effect of arazyme-interleukin-13 (Ara-IL13) fusion protein on GBM cells. Experimental approach: At first, the araA-IL13 chimeric gene in the pET28a (+) vector was designed and synthesized. After transformation into Escherichia coli BL21 (DE3), the chimeric gene was verified by colony polymerase chain reaction. Expression optimization and purification of the AraA-IL13 fusion protein was performed and subsequently evaluated by 10% SDS-PAGE. The protein was purified and concentrated using the Amicon® Ultra- 15 centrifugal filter unit. The presence of AraA-IL13 was investigated by the western blotting technique. The enzyme was evaluated for proteolytic activity after purification on skim milk agar. The cytotoxic effect of the AraA-IL13 fusion protein was evaluated by MTT assay on U251 and T98G cell lines in vitro. Findings/Results: The chimeric protein had no proteolytic activity on skim milk agar despite high expression. Furthermore, no cytotoxic effect of this fusion protein (up to 400 µg/mL) was observed on the U251 and T98G cell lines. Conclusion and implications: The lack of proteolytic activity and cytotoxic effect of AraA-IL13 may be due to the disruption of the three-dimensional structure of the protein or the large structure of the arazyme coupled with the ligand and the lack of proper folding of the arazyme to make the active site of the enzyme inaccessible.

Improving the Cytotoxic Activity of Hinokitiol from Drug-Loaded Phytosomal Formulation Against Breast Cancer Cell Lines.

Background: This study investigates the influence of various formulation parameters on the characteristics of hinokitiol-loaded phytosomes and evaluates their anticancer potential against breast cancer cells. Materials and Methods: Phytosomal nanoparticles were prepared and characterized for size, zeta potential, and entrapment efficiency. Morphological analysis was conducted using optical microscopy and transmission electron microscopy (TEM). The solubility of hinokitiol at different pH levels was determined, and the in vitro release profile of the optimized phytosomes was assessed. Cytotoxicity assays were performed to evaluate the anticancer efficacy against breast cancer cell lines, and apoptosis induction was examined using Annexin V/propidium iodide staining. Cell cycle analysis was conducted to assess the impact on cell cycle progression. Results: The optimized phytosomes demonstrated a size range of 138.4 ± 7.7 to 763.7 ± 15.4 nm, with zeta potentials ranging from -10.2 ± 0.28 to -53.2 ± 1.06 mV and entrapment efficiencies between 29.161 ± 1.163% and 92.77 ± 7.01%. Morphological characterization confirmed uniformity and spherical morphology. Hinokitiol solubility increased with pH, and the release from the optimized phytosomes exhibited sustained patterns. The formulated phytosomes showed superior cytotoxicity, with lower IC50 values compared to pure hinokitiol. Treatment induced significant apoptosis and cell cycle arrest at the G2/M and S phases. Conclusion: Hinokitiol-loaded phytosomes demonstrate promising anticancer efficacy against breast cancer cells, highlighting their potential as targeted therapeutic agents for breast cancer therapy.

Phytochemical composition, antimicrobial, antioxidant, and wound healing activities of Thermopsis turcica.

The antioxidant, antimicrobial, anticarcinogenic, wound healing activities and phenolic substance profile of aqueous extracts prepared using branch, leaf, flower parts and above-ground parts of Thermopsis turcica were determined in the study. The analyses indicate that the total phenolic substance contents and total antioxidant status are higher in the mix, flower, and leaf extracts. The extracts reduced cell viability in HGF cells more than in A549 cells. It shows that the extract has low anticarcinogenic activity in A549 cells. Flower extract had the highest wound closure rate. Quinic acid, cyranoside and luteolin were found in high concentrations in all extracts with LC/ESI-MS/LC analysis. It has been determined that the flower extract of the species is the most critical part showing antioxidant, antimicrobial, cytotoxic and wound healing properties. While the leaf and mix extracts stand out with their antioxidative and antimicrobial properties, the branch extract is effective in wound healing.

Advancing Food Packaging: Exploring Cyto-Toxicity of Shape Memory Polyurethanes.

Cytotoxicity is a critical parameter for materials intended for biological applications, such as food packaging. Shape-memory polyurethanes (SMPUs) have garnered significant interest due to their versatile properties and adaptability in synthesis. However, their suitability for biological applications is limited by the use of aromatic isocyanates, such as methylene diphenyl 4,4'-diisocyanate (MDI) and toluene diisocyanate (TDI), which are commonly used in SMPU synthesis but can generate carcinogenic compounds upon degradation. In this study, thermo-responsive shape-memory polyurethanes (SMPUs) were synthesized using poly(tetramethylene ether) glycol (PTMG) and castor oil (CO) as a chain extender with four different isocyanates-aromatic (MDI and TDI), aliphatic (hexamethylene diisocyanate [HDI] and isophorone diisocyanate [IPDI])-to evaluate their impact on polyurethane cytotoxicity. Cytotoxicity assays were conducted on the synthesized SMPU samples before and after exposure to light-induced degradation. The results showed that prior to degradation, all samples exhibited cell proliferation rates above 90%. However, after degradation, the SMPUs containing aromatic isocyanates demonstrated a drastic reduction in cell proliferation to values below 10%, whereas the samples with aliphatic isocyanates maintained cell proliferation above 70%. Subsequently, the influence of polyol chain length was assessed using PTMG, with molecular weights of 1000, 650, and 250 g·mol-1. The results indicated that the SMPUs with longer chain lengths exhibited higher cell proliferation rates both before and after degradation. The thermal and mechanical properties of the SMPUs were further characterized using thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and thermomechanical analysis (TMA), providing comprehensive insights into the behavior of these materials.

In silico approximation to aflatoxin B1 metabolism and sensitivity in commercial poultry species based on empirical mathematical equations.

Enzyme kinetic parameters for aflatoxin B1 metabolism have been reported for chicken, quail, turkey and duck, but an integrated in silico model has not been proposed. Both enzyme-catalyzed reactions and spontaneous reactions were modeled in the CellDesigner software and results were adjusted to Hill, Rational and Hoerl models. Results revealed that the higher amount of aflatoxin B1 epoxide produced in a short lapse of time and a low production of epoxide conjugated to glutathione explains the severe genotoxic effect of aflatoxin B1 in duck. Also, the higher amount of aflatoxicol produced is time-associated to aflatoxin B1 resistance in chicken. Finally, the cytotoxic effects in quail and duck are caused by a large aflatoxin B1 dialdehyde production in a short period of time.

Cyclocarysaponins A-J, dammarane-type triterpenoid glycosides from the leaves of Cyclocarya paliurus.

Ten previously undescribed dammarane-type triterpenoid glycosides, cyclocarysaponins A-J (1-10), were isolated from the leaves of Cyclocarya paliurus (Batal.) Iljinskaja. The structures of these compounds were characterized through detailed spectroscopic analysis, including 1D and 2D nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The cytotoxic activities of all isolates were assessed against five human cancer cell lines (Bel-7402, Caski, BGC-823, A2780, and HCT-116). Of the tested compounds, compounds 1, 7, and 9 exhibited selective cytotoxicity against one or more human cancer cell lines.

Single-cell transcriptome analysis reveals atypical monocytes circulating ahead of acute graft-versus-host disease clinical onset.

Acute graft-versus-host disease (aGVHD) represents the rejection of the recipient's skin, gut, and liver tissues of an allogeneic hematopoietic stem cell transplantation (HSCT) by the donor T-cells. The onset of aGVHD is often rapid and its evolution is unpredictable. We undertook the single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) collected before aGVHD clinical onset in three patients and from one patient afterward. We used four HSCT recipients who remained free of aGVHD as controls. This analysis unveiled the presence of particular subpopulations of circulating monocytes and cytotoxic T cells (CTLs) in pre-aGVHD samples up to 18 days before clinical disease. These pre-aGVHD monocytes were characterized by an upregulation of the M2 polarity marker CD163 and the transmembrane protein SIGLEC1/CD169. At the same time, their CTL counterparts stood out for the upregulation of the CXCL10 receptor CXCR3 and the antigenic stimulation marker CD70. The occurrence of CD163/SIGLEC1 co-expressing monocytes upstream of aGVHD onset was validated using transcriptomic data from an independent cohort and by flow cytometry in additional blood samples. These findings point to potential early diagnostic tools and preventive therapeutic strategies for aGVHD.

Quassinoids as Promising Anti-cancer Agents.

The use of current anticancer drugs is hampered by significant side effects and high costs. In the pursuit of safer, more effective, and affordable options, researchers have turned to nature as a valuable source of potential anticancer compounds. Quassinoids, a class of natural terpenoids, have garnered attention for their anticancer properties. This comprehensive review aims to shed light on natural quassinoids and their anticancer effects, offering valuable insights for researchers dedicated to the development of novel anticancer therapeutics.

Sustained antiviral response against in vitro HIV-1 infection in peripheral blood mononuclear cells from people with chronic myeloid leukemia treated with ponatinib.

HIV-1 infection cannot be cured due to long-lived viral reservoirs formed by latently infected CD4+ T cells. "Shock and Kill" strategy has been considered to eliminate the viral reservoir and achieve a functional cure but the stimulation of cytotoxic immunity is necessary. Ponatinib is a tyrosine kinase inhibitor (TKI) clinically used against chronic myeloid leukemia (CML) that has demonstrated to be effective against HIV-1 infection in vitro. Several TKIs may induce a potent cytotoxic response against cancer cells that makes possible to discontinue treatment in people with CML who present long-term deep molecular response. In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. Participants were followed-up for an additional 12 months in the absence of treatment. PBMCs were obtained at different time points and then infected in vitro with HIV-1. The rate of infection was determined by quantifying the intracellular levels of p24-gag in CD4+ T cells. The levels of p24-gag+ CD4+ T-cells were lower when these cells were obtained during and after treatment with ponatinib in comparison with those obtained during treatment with imatinib. Cytotoxicity of PBMCs against HIV-infected target cells was significantly higher during treatment with ponatinib than during treatment with imatinib, and it was maintained at least 12 months after discontinuation. There was a significant negative correlation between the lower levels of p24-gag+ CD4+ T-cells and the higher cytotoxicity induced by PBMCs when cells were obtained during and after treatment with ponatinib. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir.

An abnormal increase in CD26(-)CD28(-) cytotoxic effector CD4 and CD8 T cell populations in patients with systemic lupus erythematosus.

CD26 is a human T cell costimulatory molecule as well as a T cell subset marker, and increase of CD26+ T cells in inflamed tissues and peripheral blood has been reported in diverse autoimmune diseases. In contrast, our group has previously shown that levels of circulating CD26+ T cells are decreased in patients with systemic lupus erythematosus (SLE), although the role of reduced CD26 T cell surface expression in SLE pathology remains to be elucidated. In the present study, we conducted CD26-based T cell subset analyses utilizing peripheral blood mononuclear cells from 57 SLE patients and 31 healthy adult volunteers. We show that the increase in CD26(-) T cell population reflects the abnormal expansion of CD26(-)CD28(-) cytotoxic subsets of both CD8 T cells and CD4 T cells in SLE patients. Single cell RNA sequencing analysis of the CD26(-)CD28(-) CD4 and CD8 T cell populations reveals unique characteristics with similarities to natural killer T cells. In addition, the level of CD26(-)CD28(-) T cells is increased in some active stage SLE patients with renal manifestation. Meanwhile, effect of prednisolone treatment on these populations varies from patient to patient, with levels of these cytotoxic effector populations still being elevated in some inactive stage SLE patients. Taken together, our data suggest that analysis of these populations in SLE may be a useful tool to classify this markedly heterogeneous condition.

Risk factors for relapse of immune-related pneumonitis after 6-week oral prednisolone therapy: a follow-up analysis of a phase II study.

BACKGROUND: Immune-related pneumonitis (irP) is one of the most important immune-related adverse events caused by immune checkpoint inhibitors (ICIs). After corticosteroid therapy irP frequently relapses, which can interfere with cancer therapy. However, risk factors for irP relapse are unknown. METHODS: This study was a follow-up analysis of a phase II study that evaluated 56 patients with grade ≥ 2 irP treated with oral prednisolone, 1 mg/kg/day, tapered over 6 weeks. Clinical factors including patient characteristics, blood test findings, and response to prednisolone therapy were assessed to identify risk factors for irP relapse using the Fine-Gray test. RESULTS: Among 56 patients with irP, 22 (39.3%) experienced irP relapse after 6 weeks of prednisolone therapy during the follow-up observation period. Radiographic organising pneumonia (OP) pattern and duration to irP onset ≥ 100 days from ICI initiation were determined to be significant risk factors for irP relapse in a multivariate Fine-Gray test (hazard ratio [HR] = 3.17, 95% CI 1.37-7.32, p = 0.007, and HR = 2.61, 95% CI 1.01-6.74, p = 0.048, respectively). Other patient characteristics, blood test findings, irP severity, and response to prednisolone therapy were not associated with irP relapse. CONCLUSIONS: In irP patients treated with 6-week prednisolone tapering therapy, OP pattern and duration to irP onset ≥ 100 days were associated with relapse risk. Assessment of the risk factors for irP relapse will be helpful for irP management.

PI3K/AKT/mTOR and PD­1/CTLA­4/CD28 pathways as key targets of cancer immunotherapy (Review).

T cells play an important role in cancer, and energy metabolism can determine both the proliferation and differentiation of T cells. The inhibition of immune checkpoint molecules programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) are a promising cancer treatment. In recent years, research on CD28 has increased. Although numerous reports involve CD28 and its downstream PI3K/AKT/mTOR signaling mechanisms in T cell metabolism, they have not yet been elucidated. A literature search strategy was used for the databases PubMed, Scopus, Web of Science and Cochrane Library to ensure broad coverage of medical and scientific literature, using a combination of keywords including, but not limited to, 'lung cancer' and 'immunotherapy'. Therefore, the present study reviewed the interaction and clinical application of the PD-1/CTLA-4/CD28 and PI3K/AKT/mTOR pathways in T cells, aiming to provide a theoretical basis for immunotherapy in clinical cancer patients.

The hallmarks of cancer immune evasion.

According to the widely accepted "three Es" model, the host immune system eliminates malignant cell precursors and contains microscopic neoplasms in a dynamic equilibrium, preventing cancer outgrowth until neoplastic cells acquire genetic or epigenetic alterations that enable immune escape. This immunoevasive phenotype originates from various mechanisms that can be classified under a novel "three Cs" conceptual framework: (1) camouflage, which hides cancer cells from immune recognition, (2) coercion, which directly or indirectly interferes with immune effector cells, and (3) cytoprotection, which shields malignant cells from immune cytotoxicity. Blocking the ability of neoplastic cells to evade the host immune system is crucial for increasing the efficacy of modern immunotherapy and conventional therapeutic strategies that ultimately activate anticancer immunosurveillance. Here, we review key hallmarks of cancer immune evasion under the "three Cs" framework and discuss promising strategies targeting such immunoevasive mechanisms.