Antibody-drug conjugates (ADCs) are a promising cancer therapy for targeted delivery of drugs to tumor cells. However, resistance to ADCs remains a challenge, necessitating the exploration of combination therapies. A strong biological theory suggests that ADCs interact with cancer cells and immune cells by triggering mechanisms such as immunogenic cell death, dendritic cell activation, and memory T-cell activation, resulting in long-term anti-tumor immunity and ultimately potential synergistic effects with immunotherapy. Based on extensive and reliable preclinical data, several clinical trials are currently combining ADCs with immune checkpoint inhibitors (ICIs) for the treatment of various cancers, including breast, gastric, and non-small-cell lung cancers, to evaluate the safety and anti-tumor activity of the combination therapy. Preliminary evidence from early clinical trials has reported more effective efficacy data. This paper reviews the combination of ADCs and immunotherapy, highlights the key mechanisms by which the two act synergistically, and summarizes the available clinical evidence against different ADCs targets. The paper also explores the re-challenges used for combination therapies and optimized design options for ADCs drugs.

Reactive oxygen species (ROS)-mediated pyroptosis provides a robust strategy for overcoming apoptosis resistance in breast cancer therapy. Nevertheless, the low efficiency of pyroptosis remains an undeniable challenge. Overcoming this obstacle necessitates the creation of innovative approaches and nanocatalysts to boost ROS generation. Herein, the distinct lanthanum-doped BiFeO3 (La-BFO) piezoelectric nanozymes are rationally designed and engineered for the specific cell pyroptosis of breast cancer through inducing the amplified production of ROS and releasing La ions.

Doxorubicin (DOX), a common chemotherapeutic agent, is often associated with dose-limiting hepatotoxicity. Alamandine, a peptide of the renin-angiotensin system, has shown antioxidant and anti-inflammatory properties that may counteract these adverse effects.

Human hepatocellular carcinoma (HCC) is recognized as one of the leading causes of death globally and is resistant to several anticancer drugs. As a result, it is critical to identify more effective druggable therapies. Metal oxide nanoparticles (MO-NPs), especially nanocomposites, have recently received much attention owing to their potential applications in cancer therapy. In this study, we synthesized zinc oxide (ZnO) and copper oxide (CuO) nanocomposites in different ratios (N1, N2, and N3). We evaluated their cytotoxicity against two HCC cell lines (HepG2 and HuH-7) and one normal liver cell (BNL), compared with Sorafenib as a standard therapy. Then, we investigated the potential underlying mechanisms of anticancer action employing flow cytometry, migration assay, and western blot. The results showed that the nanocomposite with an equal ratio of both ZnO and CuO-NPs (N1) exhibited the highest cytotoxic activity on the HuH7 cell line while exerting no detrimental impact on normal rat liver epithelial cells. Further investigation into the toxicity mechanisms of N1 revealed three modalities of induced cell death (apoptotic, necrotic, and autophagic) along with S- and G2/M cell cycle arrest, suggesting mitotic catastrophe. Furthermore, N1 displayed potent anti-migratory activity, surpassing sorafenib, upregulated the protein level of autophagy marker beclin-1, while downregulated the protein level of EMT-marker vimentin. Overall, our findings showed that combining ZnO-NPs and CuO-NPs is more intriguing in combating HCC, providing prospective guidance for evolving liver cancer therapy employing bimetallic NPs.

The long-term effects of doxorubicin (DOX) chemotherapy on thymic immune function in childhood cancer survivors remain inadequately understood. This study explores the immediate and delayed impacts of low-dose DOX on thymic immune populations using a juvenile mouse model. Male mice received intraperitoneal DOX injections (4 mg/kg/week) for three weeks, with evaluations performed at one- and five-weeks post treatment. Thymic samples were collected and analyzed using multi-parameter flow cytometry to assess changes in immune cell composition and phenotype. Additionally, real-time polymerase chain reaction (RT-PCR) was employed to measure gene expression of cytokines and senescence markers. One week after DOX administration, significant thymic atrophy was evident. While mature CD3+CD4+ T-cell frequency remained unchanged, CD3+CD8+ T-cells significantly increased, suggesting differential effects on T-cell subsets. PD1+ expression increased across naïve and memory CD4+ T-cell subsets, suggesting activation or exhaustion. Additionally, Ki67+ expression was elevated in naïve and memory CD8+ T-cells, indicating enhanced proliferation. Gene expression analysis revealed upregulation of Foxn1, Pax1, Ifnγ, and Il7 whereas Il6 and Il17 were downregulated. Furthermore, Cdkn1a (p21) expression was elevated, suggesting immune dysregulation and early immunosenescence. At five weeks, thymic weight rebounded; however, T-cell subsets displayed persistent perturbations. Central memory and effector memory CD4+ T-cells were reduced, while naïve CD4+ T-cells showed increased Ki67+ expression. In contrast, CD8+ T-cells subsets remained largely unchanged, except for a decrease in central memory cells. Although expression of thymus-related genes was normalized, p21 expression remained elevated, suggesting lingering immunosenescence. These findings highlight the complex effects of DOX, including acute thymic atrophy due to T-cell depletion, and a delayed recovery with persistent immunosenescence, underscoring the need for strategies to preserve immune function in childhood cancer survivors.

Targeting the programmed death (ligand)-1 (PD-1/PD-L1) axis with immune checkpoint inhibitors (ICIs), like pembrolizumab, has improved cancer survival. Unfortunately, the optimal dose remains unknown and less than 50 % of patients respond. Understanding PD-1 receptor pharmacology and developing early-response biomarkers are crucial to personalize therapy. We hypothesize that characterizing individual pre-treatment variability in immune responses to pembrolizumab will enhance PD-1 receptor pharmacology insights and improve treatment response prediction. Hence, this study evaluates the performance of a newly developed ex vivo immunopharmacological bioassay under healthy and pathological states.

Triple-negative breast cancer (TNBC) is one of the most heterogeneous and menacing forms of breast cancer, with no sustainable cure available in the current treatment landscape. Its lack of targets makes it highly unresponsive to various treatment modalities, which is why chemotherapy continues to be the primary form of treatment, despite the high rates of patients developing chemoresistance. In recent years, however, there has been significant progress in identifying and understanding the role of several aspects that might contribute to genomic instability and other hallmarks of cancer, including cellular proteins, immune targets, and epigenetic mechanisms, which are desirable as they permit reversibility easier than the often-adamant genetic changes.

Immune checkpoint inhibitors (ICI) targeting CTLA-4 and PD-1 have shown remarkable antitumor efficacy, but can also cause immune-related adverse events, including checkpoint inhibitor-induced liver injury (ChILI). This multi-omic study aimed to investigate changes in blood samples from treated cancer patients who developed ChILI. PBMCs were sequenced for by transcriptomic and T cell receptor repertoire (bulk and single-cell immune profiling), and extracellular vesicle (EV) enrichment from plasma was analyzed by mass spectroscopy proteomics. Data were analyzed by comparing the ChILI patient group to the control group who did not develop ChILI and by comparing the onset of ChILI to pre-ICI treatment baseline. We identified significant changes in T cell clonality, gene expression, and proteins in peripheral blood mononuclear cells (PBMCs) and plasma in response to liver injury. Onset of ChILI was accompanied by an increase in T cell clonality. Pathway analysis highlighted the involvement of innate and cellular immune responses, mitosis, pyroptosis, and oxidative stress. Single-cell RNA sequencing revealed that these changes were primarily found in select T cell subtypes (including CD8 + effector memory cells), while CD16 + monocytes exhibited enrichment in metabolic pathways. Proteomic analysis of plasma extracellular vesicles showed enrichment in liver-associated proteins among differentially expressed proteins. Interestingly, an increase in PBMC PD-L1 gene expression and plasma PD-L1 protein was also found to be associated with ChILI onset. These findings provide valuable insights into the immune and molecular mechanisms underlying ChILI as well as potential biomarkers of ChILI.Trial registration number NCT04476563.

One in five chronic myeloid leukemia (CML) patients experiences such intolerability that they switch tyrosine kinase inhibitor (TKI) treatment within 3 years. Information on tolerability is needed to guide shared decision-making. However, an overview of symptoms patients experience per TKI is lacking, and physician-graded toxicity underestimates patients' experiences.

To explore the clinical value of transcatheter arterial chemoembolization (TACE) using a temperature-sensitive liquid embolic agent for the interventional treatment of primary hepatocellular carcinoma.

The combination of immune checkpoint inhibitors (ICIs) and radiotherapy (RT) has shown promise in improving the outcomes in non-small cell lung cancer (NSCLC) patients; however, the potential benefits and predictors remain unclear. This meta-analysis evaluated the efficacy and safety of ICI + RT compared to RT or ICI monotherapy and explored the potential factors influencing the treatment efficacy of this combination therapy. The efficacy was assessed using hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS). Multivariable data were pooled, and subgroup analyses were performed to identify the influencing factors. The safety was evaluated using odds ratios (OR) of any grade and grade ≥3 treatment-related adverse events (TRAEs). ICI + RT significantly improved the OS of patients with brain metastases compared to RT alone (HR = 0.42; P = 0.004). The combination therapy showed improved OS (HR = 0.71; P < 0.001) and PFS (HR = 0.69; P < 0.001) compared to ICI monotherapy. Subgroup analysis revealed significant survival benefits in metastatic and oligometastatic NSCLC patients receiving sequential ICI after RT and those undergoing intracranial or extracranial RT. ICI + RT increased the incidence of any grade TRAEs (OR = 1.3; P = 0.007) compared to ICI alone; no significant difference was observed in grade ≥3 TRAEs. ICI + RT provides significant survival benefits over monotherapy in advanced NSCLC, with a manageable toxicity profile. Prospective trials are needed to validate these findings and refine patient selection for combination therapy.

IL-33 is an epithelial-derived alarmin with various roles in cancer. In melanoma, endogenous and exogenous IL-33 exert anti-tumor effects through the stimulation of several immune effector cells. In this study, we explored the combination of IL- 33 with Decitabine (DAC), a DNA methylation inhibitor that promotes immune recognition by re-activating silenced genes, for melanoma treatment.

The effect of frequent whole-body CT scans during immune checkpoint inhibitor (ICI) therapy on patients' anti-tumor immunity.

The substantial apprehension facing young cancer patients revolves around the onset of chemotherapy-induced premature ovarian failure (POF), primarily linked to damage inflicted upon granulosa cells (GCs). The inquiry delves into the protective role of extracellular vesicles (EVs) derived from human umbilical cord mesenchymal stem cells (hUCMSCs) in mitigating chemotherapy-induced ovarian failure. Specifically, we investigated the mechanism by which hUCMSC-EVs deliver the long non-coding RNA (lncRNA) HCP5 to regulate DNA damage repair in GCs via the miR-20a-5p/YAP1 axis. The detection of differentially expressed lncRNAs in GC injury resulting from cyclophosphamide (CP) was conducted through transcriptome sequencing. hUCMSC-EVs were isolated, characterized, and co-cultured with CP-injured GCs. Functional assays such as CCK-8, TUNEL, and ELISA were performed to evaluate GC viability, apoptosis, and ovarian endocrine function. Experimental validation of the interactions involving HCP5, miR-20a-5p, and YAP1 was achieved through performing luciferase reporter assays, RNA immunoprecipitation experiments, and Western blot (WB) analyses. HCP5 was significantly enriched in hUCMSC-EVs and effectively delivered into GCs. This resulted in improved GC viability, reduced apoptosis, and enhanced DNA repair. Mechanistically, HCP5 sponged miR-20a-5p, leading to the upregulation of YAP1, which in turn mitigated CP-induced GC damage. In vivo experiments further demonstrated that hUCMSC-EVs prevented CP-induced POF through modulation of the HCP5-miR-20a-5p-YAP1 axis. Our research underscores the therapeutic potential of hUCMSC-EVs in delivering HCP5 to promote DNA repair in GCs, thereby preventing chemotherapy-induced POF. This study provides a novel molecular framework for future therapeutic strategies aimed at protecting ovarian function during chemotherapy.

Graphene is a nanomaterial used in health and oncology settings. However, several reports have raised the alarm about potential toxicity. This study addressed this concern and determined the in vitro cytotoxicity of few-layer graphene (FLG) flakes produced in bespoke ultrasonic reactors using benign methods. The use of graphene flakes as a potential sensitising agent and a carrier for drug delivery in cancer cells was evaluated. To this end, aqueous based FLG suspensions were systematically characterised using UV-Vis, Raman spectroscopy and High-resolution Transmission electron microscopy (HR-TEM). Cell toxicity characterisation (e.g., cell viability assays using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) and cell membrane integrity) of FLG in water were performed together with charge coupled device (CCD) and second harmonic generation (SHG) imaging of live cells in graphene solutions. Collectively, our findings show that NIH 3T3 mouse fibroblast and human fibroblast cells survival was higher than 80% and 90%, respectively upon treatment with the FLG fraction (~ 16 µg/ml ) recovered after centrifugation at 2000 revolutions per minute (RPM). In contrast, the cervical cancer cell line HeLa exposed to similar concentrations of FLG flakes resulted in approximately 30% cell death arguing in favour of a sensitising effect in cervical cancer cells.

Poly (ADP-ribose) polymerase (PARP) inhibitors have improved the prognosis of homologous recombination deficient (HRD) ovarian cancer (OC), while effective therapeutic strategies for HR-proficient (HRP) OC still need to be established. This study investigates senescence-mediated inflammation as a novel mechanism of action for PARP inhibitors in HRP cancers. Transcriptome analyses were performed in olaparib-treated HeLa cells as a HRP model. Interferon regulatory factor-Lucia luciferase (IRF-Luc) reporter activity was assessed. The effects of PARP inhibitors on senescence-like phenotypes were assessed in seven HRP cancer cell lines, based on morphological changes, senescence-associated β-galactosidase (SA-β-GAL) activity, cellular granularity, and senescence-associated secretory phenotype (SASP)-related gene expression. Peripheral blood mononuclear cell (PBMC) migration assays were also performed with the conditioned medium in treatment with the PARP inhibitor. Transcriptome analyses revealed numbers of inflammatory cytokine- and chemokine-related pathways were significantly upregulated in olaparib-treated HeLa cells, which were confirmed by IRF-Luc reporter assays. The PARP inhibitors induced senescent phenotypes in HRP cancer cell lines: flattened and enlarged morphology, increased SA-β-GAL activity, elevated cellular granularity, and upregulated expressions of SASP-related genes (e.g., IL1B, IL6, and CXCL10). Furthermore, in vitro migration assays revealed that PARP inhibitor-treated HRP cancer cells attracted PBMCs more abundantly, suggesting the potential for recruiting immune cells to HRP cancer cells through senescence-mediated immunological activation. Our findings suggest that PARP inhibitors recruit immune cells to HRP cancer cells, potentially activating immune responses in the tumor microenvironment, providing new insights into the clinical benefits of PARP inhibitors in immunotherapy for patients with HRP OC.

To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours.

The efficacy of immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC) is limited by heterogeneity in individual responses to therapy. The heterogeneous phenotypes and crucial roles of cancer-associated fibroblasts (CAFs) in immunotherapy resistance remain largely unclear.

Cancer is a leading cause of death worldwide, and despite the introduction of new therapeutic approaches for advanced cases aimed at improving patient survival, only a subset of patients benefits from a complete response. In this context, there is a growing need for new cancer biomarkers and therapeutic strategies, and the use of Extracellular Vesicles (EVs) has been widely explored in various approaches. As circulating lipid-bilayer particles carrying a variety of biological information from tumor cells, EVs can be employed as good biomarkers of diagnosis, prognosis, therapy evaluation, and as adjuvants in cancer treatment. In this review, we provide a brief overview of the different types of EVs and their biogenesis and discuss how tumor-derived EV cargo can serve as a potential biomarker in clinical settings through liquid biopsy. We also highlight recent advances in EV nanoengineering and their potential as adjuvants in cancer treatment. Finally, we discuss the key unknowns, gaps, and bottlenecks that must be addressed to fully integrate EVs into precision oncology.

The chromodomain protein CBX2 binds directly to histone H3 trimethylation at lysine 27 (H3K27me3) and is a component of polycomb repressive complex 1 (PRC1). CBX2 plays a pivotal role in transcriptional repression by acting as a reader protein that recognizes H3K27me3. In this study, we performed in silico screening based on the crystal structure of CBX2 to identify small molecule compounds that target the chromodomain of CBX2. The ability of the selected compounds to inhibit the interaction between CBX2 and histone H3 in cells was validated. After three rounds of in silico screening, CG3-46 was ultimately identified as the most potent CBX2 inhibitor in this study. CG3-46 inhibited the growth of the triple-negative breast cancer cell line MDA-MB-231, accompanied by an increase in the expression of a CBX2 target gene. Our results indicate that CG3-46 represents the first nonpeptide small molecule inhibitor of CBX2, which not only serves as a valuable chemical tool for elucidating the role of CBX2 in cellular epigenetic regulation but also as a starting compound for the development of CBX2-targeted therapeutics for triple-negative breast cancer.