Search Results (851)

Breast cancer relapse in bone is a significant clinical problem that is experienced in ~70–80% of patients with late-stage breast cancer. This condition commonly occurs 5–10+ years following surgical removal of the primary tumour. The long latency seen prior to relapse in bone is a result of tumour cell dormancy. Once disseminated to the bone, tumour cell interaction with the bone metastatic niche (endosteal niche and endovascular cells) maintains cells in a dormant state until changes to the local environment activate the niche to support outgrowth. Amassing evidence suggests that cytokines are key regulators of the bone metastatic niche, controlling bone homing and metastatic outgrowth. Pro-inflammatory cytokines, including IL-1β, IL-6, IL-8, TGFβ and RANKL, play crucial roles in attracting tumour cells to bone. Furthermore, these cytokines act in conjunction with IFN, VEGF, TGF, PTHrP, FGF, OPG and various chemokines to regulate expansion of the niche, facilitating tumour cell escape from dormancy and promoting the “vicious cycle of bone metastasis”. Here, we review the current literature to provide an up-to-date understanding of how interactions between cytokine signalling cascades regulate the bone metastatic niches to promote homing, dormancy or metastatic outgrowth of breast cancers. Because breast cancers are predominantly osteolytic, this review focuses on dormancy and metastatic outgrowth associated with lytic disease in addition to current advances in novel therapeutics aimed at preventing this condition through targeting dormant cells. Full article

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour’s capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, β2-microglobulin (β2-m), or interferon-γ (IFN-γ) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies. Full article

Human immunodeficiency virus (HIV) is an enveloped virus with a remarkable capacity for genetic diversification, enabling rapid escape from host immune responses and therapeutic interventions. Despite extensive global efforts, the development of an effective vaccine has remained elusive owing to the virus’s high genetic variability and antigenic diversity. Consequently, considerable effort has been directed toward the development of therapeutic agents targeting viral entry, reverse transcriptase, integrase, protease, and more recently, capsid. Although antiretroviral therapy (ART) remains the cornerstone of HIV treatment, it is associated with challenges including drug resistance, adverse side effects, and limitations in access and affordability. Targeting viral entry offers distinct advantages by blocking infection at the earliest stage of the viral life cycle and enabling the neutralization of free virions, as well as Fc-mediated elimination of HIV-infected cells in some cases. This review highlights promising protein-based HIV entry inhibitors that have demonstrated efficacy in preclinical studies, and discusses ongoing efforts to optimize their valency, avidity, specificity, serum half-life, effector functions, and production platforms to improve their therapeutic potential and economic feasibility. Full article

Background: Wastewater surveillance has emerged as an effective tool for population-level pathogen monitoring. Its application to mutations associated with resistance to antivirals remains comparatively underdeveloped. We assessed the wastewater epidemiology framework using SARS-CoV-2 as a model pathogen to evaluate spatial, temporal, and therapeutic class-specific resistance dynamics. Methods: We analyzed about 10,000 SARS-CoV-2-positive wastewater samples from six Ontario public health regions collected between October 2021 and July 2024. Fifty-five mutations were screened, comprising therapeutic resistance-associated mutations and a biologically distinct group of immune-evasion mutations. Mutations detected in ≥10 samples at ≥1% frequency were retained for spatiotemporal analysis using LOESS smoothing and Kruskal–Wallis testing. Results: Twelve mutations met the inclusion thresholds. S:E340D, associated with reduced susceptibility to sotrovimab was geographically widespread but transient and low-frequency. Five remdesivir-associated polymerase mutations were sporadic with sharp localized peaks, including two mutations exceeding 99% frequency in isolated catchments. Three nirmatrelvir-associated protease mutations were detected, with ORF1a:Q3452K showing significant regional variation. FLiRT and FLuQE immune-evasion mutations were most persistent and abundant. LOESS smoothing showed distinct temporal patterns among mutations, while Kruskal–Wallis testing identified significant regional variation for ORF1a:Q3452K and the three immune-evasion mutations. Conclusions: These findings demonstrate that wastewater surveillance enables population-scale monitoring of antiviral resistance and immune escape-associated mutations and offers a scalable model for broader surveillance. Full article

Background/Objectives: Glioblastoma (GBM) remains a lethal primary CNS malignancy with limited response to immunotherapy. Adoptive cellular therapy (ACT) improves survival in preclinical models, yet tumors ultimately recur. While T cell exhaustion is a common mechanism of resistance, the contribution of dendritic cell (DC) dysfunction remains unclear. We aimed to define mechanisms of immune escape following ACT, focusing on DC function and the role of hypoxia. Methods: Using a murine glioma model (KR158B-luc), mice were treated with ACT consisting of tumor RNA-pulsed DC vaccines and adoptively transferred T cells. Tumor-infiltrating immune populations were analyzed by flow cytometry. DC function was assessed using T cell activation assays. Bulk RNA sequencing and gene set enrichment analysis were performed on sorted DCs. Hypoxia was modeled in vitro, and HIF1α was perturbed using CRISPR-mediated knock-out. Results: ACT significantly increased survival but did not prevent tumor recurrence. Escaped tumors contained abundant cytotoxic, non-exhausted T cells, indicating that T cell dysfunction was not the primary driver of recurrence under ACT. Instead, tumor-associated DCs exhibited impaired T cell activation despite preserved antigen uptake. Transcriptomic analyses revealed reduced antigen presentation and co-stimulatory signaling, alongside increased expression of tolerogenic factors. ACT-treated tumors demonstrated heightened hypoxia pathway activation, with elevated HIF1α expression in DCs. Hypoxia induced DC tolerogenic programs and reduced their ability to activate T cells, an effect partially reversed by HIF1α disruption. Increased immune infiltration and inflammation following ACT further amplified hypoxia signaling and enhanced DC tolerance. Conclusions: DC dysfunction is one of the key mechanisms of immune escape following ACT in glioma. Hypoxia-driven tolerization of DCs impairs sustained anti-tumor immunity, highlighting the hypoxia–DC axis as a promising therapeutic target to enhance immunotherapy efficacy. Full article

Background: The efficacy of chemotherapy in triple-negative breast cancer (TNBC) is limited by intrinsic resistance and the tumor microenvironment (TME). Accumulating evidence reveals a mechanistic connection between programmed death-ligand 1 (PD-L1) and c-x-c motif chemokine receptor 4 (CXCR4), which dominate stroma barriers, immune escape, and cancer metastasis. Earlier studies have shown that dual suppression of c-x-c motif ligand 12 (CXCL12)/CXCR4 and programmed cell death-1 (PD-1)/PD-L1 pathways regulates extracellular matrix (ECM) deposition, activation of cancer-associated fibroblasts (CAFs), and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Methods: We combined BsNb PX4, a bispecific nanobody targeting PD-L1 and CXCR4, with paclitaxel or gemcitabine in multiple tumor cell lines and human peripheral blood mononuclear cell (hPBMC)-reconstituted xenograft mouse models. Antitumor activity was assessed by CCK-8, flow cytometry, and ELISA, and immune cell infiltration and TME remodeling were examined by immunofluorescence, immunohistochemistry, cytokine assays, and RNA-seq. Results: In MDA-MB-231 cells, BsNb PX4 synergistically enhanced paclitaxel-induced growth inhibition and apoptosis via G₂/M cycle arrest. This combinatorial strategy profoundly remodeled tumor immunity by expanding CD8⁺ T cells and depleting Foxp3⁺ CD4⁺ regulatory T cells (Tregs), while concurrently restoring T-cell cytotoxicity and skewing the cytokine balance toward an antitumor state, with elevated IFN-γ and reduced TGF-β1. Notably, compared with paclitaxel monotherapy, the combination significantly elevated intratumoral CD8⁺ T-cell infiltration, decreased Treg abundance, and exerted robust inhibitory effects on tumor growth and metastasis in humanized TNBC xenografts. Conclusions: These findings reveal that dual blockade of PD-L1 and CXCR4 acts synergistically with chemotherapy by triggering tumor cell apoptotic effects and reversing the immunosuppressive microenvironment, thereby emerging as a promising therapeutic strategy for TNBC. Full article

Gliomas, and glioblastoma in particular, remain difficult to model because molecular heterogeneity, diffuse invasion, blood–brain and blood–tumour barrier effects, immune suppression and repeated therapeutic escape converge in the same disease. Two-dimensional cultures, glioma stem cell (GSC) systems, acute tumour slices and animal models remain indispensable for mechanistic research, pharmacology and in vivo validation. Glioma organoids are complementary research platforms, not components of routine diagnostic or treatment procedures. This review links model construction, microenvironmental validation, treatment perturbation and evidence-graded interpretation. We compare patient-derived glioma organoids, GSC-derived organoids, brain organoid–glioma co-cultures, genetically engineered brain tumour organoids, and vascular-associated, immune-cell-containing and chip-based platforms. We distinguish phenotypic resemblance from physiological fidelity, tumour-intrinsic drug sensitivity from delivery competence, and proof-of-concept activity from demonstrated clinical utility. We also examine temozolomide resistance, radiotherapy, targeted and combination therapy, antiangiogenic treatment, tumour-treating fields, immune-cell therapy, oncolytic viruses, multi-omic quality control and prospective validation. Organoids should not substitute for animal models or clinical trials. Their most defensible role is to provide a patient-derived functional layer between mechanism, regimen ranking and molecular tumour-board interpretation, with claims limited by assay reproducibility, clinically achievable exposure and outcome linkage. Full article

Background: Hepatocellular carcinoma (HCC) remains a major clinical challenge due to its pronounced molecular heterogeneity and frequent resistance to conventional therapies. A key driver of therapeutic failure is the overexpression of the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-XL), which collectively maintain mitochondrial integrity and promote tumor cell survival. Methods: In this study, we evaluated a rational combination strategy targeting these complementary survival pathways using the histone deacetylase inhibitor panobinostat and the DNA-damaging agent bleomycin in HepG2 cells, a p53-functional HCC cell model. Results: In HepG2 cells, each agent alone produced only limited cytotoxicity, whereas their combination resulted in a marked and synergistic induction of apoptosis. This was shown by increased Annexin V positivity, mitochondrial outer membrane permeabilization (MOMP), and activation of caspases-8, -9, and -3 as well as cleavage of poly(ADP-ribose) polymerase (PARP). Mechanistically, panobinostat reduced Bcl-XL expression and primed mitochondria for apoptosis but simultaneously triggered compensatory upregulation of Mcl-1, representing an adaptive resistance response within this experimental system. Bleomycin effectively counteracted this escape mechanism by suppressing Mcl-1 induction, thereby lowering the apoptotic threshold and enabling mitochondrial permeabilization. In parallel, combined treatment potentiated caspase-8 cleavage, suggesting an additional caspase-8-associated apoptotic signal that amplified caspase-3/PARP execution. Pharmacological inhibition with zVAD-FMK confirmed that the observed cell death was predominantly caspase-dependent, supporting a coordinated engagement of both intrinsic and extrinsic apoptotic pathways. In summary, the combination of panobinostat and bleomycin overcomes anti-apoptotic defenses in HepG2 cells through synergistic and coordinated disruption of mitochondrial survival checkpoints and dual apoptosis pathway activation. Conclusions: By blocking a compensatory Mcl-1 escape response while simultaneously engaging extrinsic apoptosis signaling, this strategy produces potent synergistic cell death in this defined p53-functional HCC model and represents a promising mechanistic proof of concept that warrants further validation in additional molecularly diverse HCC models before broader translational conclusions can be drawn. Full article

Lipid nanoparticles (LNPs) are now the leading delivery platform for nucleic acid therapeutics, but progress in the field is measured almost entirely by physicochemical and computational proxies rather than by functional properties that determine therapeutic outcomes. This review examines six interconnected areas of LNP development: microfluidic manufacturing, lyophilization, transdermal microneedle delivery, machine learning-guided formulation design, endosomal escape biology, and protein corona-mediated organ targeting. Although these areas are often discussed separately, they are linked by a common gap between routinely measured physicochemical or computational endpoints and the biological outcomes that determine therapeutic performance. A recently developed antifouling coating substantially reduced microfluidic channel fouling under the tested conditions, although its scalability remains to be validated. Lyophilization, by contrast, still requires formulation specific re-optimization for each new lipid composition, which remains an important barrier to clinical translation. In microneedle-based delivery, physicochemical integrity after fabrication is routinely treated as a proxy for therapeutic function, although, to our knowledge, no published study has directly compared endosomal escape capacity before and after microneedle fabrication. In machine learning, model accuracy is limited primarily by fragmented, outcome-biased training data rather than by algorithm design. Independent measurements of endosomal escape efficiency converge on a low ceiling whose biological origin, whether lipid-specific or inherent to the mechanism, remains unknown. For organ-selective targeting, one mechanistic account rests on a hypothesis tested in advance; another, equally prominent, has not been shown to have been anticipated rather than reconstructed after the fact. Closing this gap is now the field’s central methodologically priority. Full article

Background: Autophagy is a process that diversely impacts the stages of both tumor initiation and progression. Elucidating the molecular mechanisms underlying autophagy and its role in tumorigenesis is a key component of anticancer strategies in both prostate cancer and other malignancies. Because advanced prostate cancer frequently exploits enhanced autophagy as a defense mechanism against therapy-induced stress (e.g., from abiraterone), the pharmacological modulation of miRNA levels presents a tremendous opportunity to block the tumor’s escape route and overcome drug resistance. Methods: A comprehensive literature review was conducted to evaluate the molecular pathways determining cancer cell survival and death. The analysis focused on the dual nature of autophagy (functioning as a ‘double-edged sword’) within the tumor microenvironment, microRNA (miRNA) regulatory networks, and the efficacy of synergistic therapeutic strategies in overcoming treatment resistance. Results: The primary focus of this paper is the dual and complex role of autophagy, which serves, on the one hand, as a cellular protective shield against metabolic stress—thereby facilitating metastasis—and, on the other hand, as a potential pathway leading to autophagic cell death. The progression of this crucial process is regulated by intricate interactions (crosstalk) with apoptotic pathways, mediated by Bcl-2 family proteins, key kinases (such as mTOR, JNK, and DAPK), and transcription factors, such as p53. Furthermore, the autophagic machinery is precisely regulated by specific miRNA molecules (e.g., miR-21, miR-141, and miR-375). These not only act as crucial intracellular modulators of autophagy but also serve as promising circulating biomarkers, enabling the monitoring of this process’s activity throughout disease progression. Conclusions: Autophagy, and in particular its modulation via miRNA signaling networks, represents a major and highly promising translational target. By directly impairing this autophagic survival mechanism, ‘double-hit’ combination therapies—integrating autophagy inhibitors (such as hydroxychloroquine or VPS34 inhibitors) with standard antiandrogen or cytotoxic agents—demonstrate promising preclinical potential in overcoming treatment resistance and favorably modulating the immune microenvironment in advanced prostate cancer. Full article

Hypertension remains a major global health burden, and control rates remain suboptimal because of poor medication adherence and limitations of existing therapies, including escape within the renin–angiotensin–aldosterone system. Zilebesiran, a first-in-class, subcutaneously administered small interfering RNA therapeutic, represents a promising advance in hypertension management. Through N-acetylgalactosamine-mediated hepatic delivery, zilebesiran selectively silences angiotensinogen (AGT) messenger RNA, the transcript encoding the common precursor of all angiotensin peptides. This upstream intervention reduces AGT production and produces durable blood pressure lowering that can persist for up to 6 months after a single dose. This review summarizes the mechanism of action of zilebesiran, its pharmacokinetic and pharmacodynamic properties, and the available phase 1 and phase 2 clinical evidence, including the KARDIA program. We also place zilebesiran within the evolving antihypertensive landscape by comparing it with aldosterone synthase inhibitors, dual endothelin receptor antagonists, and brain aminopeptidase A inhibitors. Finally, we discuss translational challenges, including reversal strategies for emergency situations, monitoring considerations, and potential roles for personalized dosing. Early-phase and phase 2 trials show dose-dependent and durable reductions in serum AGT and blood pressure with infrequent dosing; however, long-term safety, cardiovascular outcome benefit, and generalizability in diverse high-risk populations remain to be established, and zilebesiran remains investigational while phase 3 outcome testing is underway. Full article

Delayed relapse after curative-intent treatment remains difficult to explain and predict in human papillomavirus (HPV)-associated cervical cancer, including after periods of sustained remission with undetectable circulating tumor DNA (ctDNA) or circulating HPV DNA. This limitation of tumor-centered surveillance demands the evaluation of immune parameters alongside tumor-derived biomarkers. We propose “immune absence” as a hypothesis-generating, operational framework referring to the sustained reduction or non-persistence of pre-specified tumor-reactive T-cell receptor (TCR) clonotypes in serial peripheral blood samples, obtained during minimal residual disease states in which antigen exposure may be limited or intermittent. We hypothesize that this longitudinal pattern may precede molecular or clinical evidence of relapse in a subset of patients and coexist with established mechanisms, such as tumor evolution, immune escape, T-cell dysfunction, and therapeutic resistance. Integrating serial ctDNA or circulating HPV DNA measurements with tumor-reactive TCR clonotype dynamics may provide complementary information on residual tumor burden and the persistence of circulating tumor-reactive T-cell responses. Peripheral blood TCR non-detection does not establish complete loss of anti-tumor immunity and may reflect compartmentalized immunity, clonal replacement, antigenic evolution, or assay limitations. Prospective longitudinal studies are required to establish the prognostic value of this framework before clinical use. Full article

Prostate cancer remains one of the most frequently diagnosed malignancies in men worldwide, and despite favorable outcomes for localized disease, progression to castration-resistant prostate cancer (CRPC) represents a major clinical challenge associated with poor prognosis. CRPC is characterized by disease progression despite castrate levels of circulating testosterone and is most commonly diagnosed in the metastatic setting. Although the introduction of second-generation androgen receptor-targeted therapies has improved survival, resistance inevitably emerges. This review overviews the most recent findings in the field of CRPC with particular emphasis on the current understanding of the biological mechanisms of hormone-resistant cancer as well as the evidence on treatment strategies. A comprehensive literature search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar, focusing mainly on studies published between 2015 and 2025 that investigated molecular and cellular mechanisms of resistance to androgen deprivation therapy and androgen receptor (AR)-targeted treatments. Seventy-eight relevant articles were included in the final synthesis. The reviewed evidence highlights four major categories of resistance mechanisms. First, AR-dependent alterations remain predominant, including AR gene amplification, activating mutations, dysregulation of co-regulators, and expression of constitutively active AR splice variants such as androgen receptor variant 7 (AR-V7). Second, AR-independent or bypass pathways, most notably phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), wingless-related integration site (WNT)/β-catenin, mitogen-activated protein kinase (MAPK), and glucocorticoid receptor signaling, enable tumor survival despite AR blockade. Third, lineage plasticity and transdifferentiation to neuroendocrine prostate cancer represent a distinct and increasingly recognized resistance mechanism driven by loss of tumor protein 53 (TP53) and retinoblastoma 1 (RB1) and epigenetic reprogramming. Finally, additional contributors, including intratumoral androgen synthesis, metabolic reprogramming, and tumor microenvironment interactions, further support disease progression. Together, these interconnected mechanisms underscore the biological complexity of CRPC and emphasize the need for biomarker-guided, combination-based therapeutic strategies to overcome resistance and improve patient outcomes. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts and the persistence of leukemic stem cells (LSCs) within a profoundly remodeled bone marrow (BM) microenvironment. Despite advances in molecular stratification and the introduction of targeted agents, long-term outcomes remain unsatisfactory, particularly in older and high-risk patients. Increasing evidence indicates that leukemogenesis and treatment resistance are critically sustained by a permissive immune milieu, in which LSCs, myeloid-derived suppressor cells, leukemia-associated macrophages, and dysfunctional T and NK cells shape an immunosuppressive “leukemic niche.” This evolving understanding has renewed interest in immune-based strategies capable of restoring effective antitumor immunity. Bispecific antibodies (bsAbs) are engineered molecules designed to engage AML-associated antigens while simultaneously recruiting and activating immune effector cells, most commonly T cells or NK cells. By promoting immune synapse formation independently of major histocompatibility complex expression and conventional co-stimulatory pathways, bsAbs can overcome several mechanisms of immune escape. In this review, we summarize the biological rationale for immunotherapy in AML, with a focus on the role of the BM microenvironment and immune dysregulation. We then discuss the structural and functional properties of IgG-like and non-IgG-like bsAbs, key antigenic targets such as CD33, CD123, CD70 and others, and the main T-cell- and NK-cell-engaging platforms under clinical investigation. Finally, we highlight emerging clinical data, principal toxicities, and the challenges of integrating bsAbs into existing treatment algorithms, including combinations with hypomethylating agents, BCL-2 inhibitors, and allogeneic stem cell transplantation. A deeper understanding of AML immune biology and antigen expression patterns will be essential to optimize bsAb design, maximize therapeutic benefit, and minimize on-target off-tumor toxicity. Full article

Most patients with solid tumors do not respond to immune checkpoint blockade, and inadequate T cell infiltration of the tumor parenchyma is the dominant mechanism of primary resistance. Oncolytic viruses address this problem by a distinct route: they replicate selectively within tumor cells, produce immunogenic cell death, and convert infected cells into local sources of any encoded transgene. Most armed designs to date have carried cytokine or checkpoint-antibody payloads, and chemokines have attracted comparatively little attention despite bearing directly on the trafficking bottleneck. This review synthesizes the preclinical literature on chemokine-armed oncolytic viruses across three receptor axes: CXCR3 (CXCL9, CXCL10, CXCL11), CCR5 (CCL5/RANTES), and CCR7 (CCL19). The accumulated evidence indicates that therapeutic outcome depends less on the chemokine payload itself than on the interaction between payload and viral backbone. CXCL11 outperforms its sister CXCR3 ligands not through intrinsic potency but because it is non-redundant with the endogenous chemokines induced by vesicular stomatitis virus and vaccinia, and because it largely escapes proteolytic cleavage by dipeptidyl peptidase 4 (DPP4). CCL5 has shown the most consistent activity in dual-payload designs that pair chemotaxis with a T cell survival cytokine such as IL-15. CCL19, which addresses lymphoid organization rather than effector recruitment, rests on a single published construct. One evidence gap is central: no head-to-head comparison of chemokine payloads within a single viral platform has been published. We therefore propose a translational decision framework that aligns chemokine selection with the immune contexture of the target tumor. Full article