Cancer immunotherapy targeting the PD-1/PD-L1 pathway has demonstrated efficacy across a range of common solid tumors and some hematopoietic malignancies. Despite these groundbreaking successes, the clinical development of other 'checkpoint inhibitors' targeting molecules like TIM-3, TIGIT, ICOS and others, has largely fallen short, often showing minimal clinical benefit even in combination with anti-PD therapy. This article explores three key hypotheses that help explain the disparity in therapeutic success: (1) the absence of tumor- specific immunosuppressive logic in many checkpoint targets, (2) the dominance-but not redundancy-of immune evasion mechanisms within the tumor microenvironment (TME), and (3) the emergence of therapy-induced resistance. This is not intended as a comprehensive review of the literature. Instead, it highlights select evidence to explain past failures and to illuminate a more strategic, biologically informed path forward.

Lung cancer remains one of the most prevalent and lethal malignancies worldwide, responsible for nearly 1.8 million deaths annually, which accounts for approximately 18.7% of global cancer-related mortality. Cisplatin, a highly effective and widely utilized anticancer drug, is particularly effective against solid tumors and serves as a cornerstone of adjuvant chemotherapy for lung cancer. Despite continuous optimization of cisplatin-based chemotherapy regimens, the emergence of cisplatin resistance frequently results in treatment failure, significantly limiting its clinical utility and therapeutic efficacy. To address this challenge, researchers have extensively investigated the biological mechanisms underlying cisplatin resistance, including impaired DNA repair pathways and inhibition of apoptosis. Among these mechanisms, epigenetic regulation-encompassing DNA methylation, histone modifications, and noncoding RNA (ncRNA) regulation-has emerged as a critical factor in mediating cisplatin resistance by modulating gene expression and signaling pathways. This review comprehensively explores the role of epigenetic mechanisms in cisplatin resistance in lung cancer, highlighting recent research findings and their potential implications for developing strategies to overcome drug resistance.

Breast cancer is the most prevalent cancer in women. Anthracyclines are commonly used as the first line of treatment, often combined with other agents, including trastuzumab. Despite their efficacy, both drugs pose a risk of cardiotoxicity, which may impair patients' quality of life (QoL) and hinder treatment persistence. Anthracycline-induced cardiotoxicity is dose-dependent and generally irreversible, whereas trastuzumab is associated with potentially reversible cardiac dysfunction. This review discusses the risk factors and biological mechanisms underlying chemotherapy-induced cardiotoxicity in breast cancer and explores effective strategies for prevention and treatment. It has been demonstrated that several cardioprotective strategies, such as treatments with angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), beta-blockers, and dexrazoxane, can help lessen cardiotoxic effects. A better understanding of cardioprotective strategies may help optimize cancer treatment without compromising cardiovascular function.

Doxorubicin is an antitumor antibiotic. It is often used in veterinary medicine to treat and extend the lives of dogs with cancer. A cardiotoxic side effect can lead to heart failure and treatment discontinuation. This systematic review and meta-analysis aimed to evaluate the drug's cardiotoxic effects on the ejection fraction (EF) of dogs in doxorubicin protocols. The search was done in eight databases, with a total of 3587 articles screened, resulting in fifteen eligible articles included. A report on the included studies' methods and results was done. It also assessed the risk of bias. Thirteen articles demonstrated cardiac changes in echocardiography with different routes of administration (intravenous and intracoronary). The intracoronary route was more toxic, and in all six studies performed, there was heart failure. The intravenous route caused heart failure in six of the nine studies. A meta-analysis showed this drug worsened heart disease. It included four studies where it significantly lowered the EF. Overall, the intervention produced a mean reduction of 21.24% in EF. This review shows doxorubicin's impact on cardiac function. It reveals the need for careful monitoring of each patient.

Brain tumors, particularly gliomas, are among the most lethal malignancies, with high mortality driven by a delayed diagnosis and limited therapeutic efficacy. A central challenge lies in the presence of the blood‑brain barrier (BBB), which severely impedes the delivery of systemically administered therapeutics to tumor sites. Addressing this clinical urgency, nanoparticle (NP)‑based delivery systems have emerged as a transformative strategy to enhance brain‑specific drug accumulation, minimize off‑target toxicity and improve treatment outcomes. The present review systematically examined the recent advances in nanocarrier technologies for targeted brain tumor therapy, including liposomes, solid lipid NPs, dendrimers, polymeric nanoplatforms and inorganic nanomaterials. The design principles, mechanisms for BBB traversal, therapeutic payload compatibility and tumor‑targeting capabilities of NP technologies demonstrated in preclinical models have also been highlighted. In addition to drug delivery, emerging applications of nanocarriers in gene therapy were explored and the impact of protein corona formation on NP behavior in vivo was discussed. Finally, current translational bottlenecks were identified and future design considerations to achieve clinically viable, precision‑targeted nanomedicines for brain tumors were outlined.

The B-cell lymphoma-2 (Bcl-2) family proteins, key regulators of apoptosis, are frequently dysregulated in cancer, tipping the balance of cell survival and apoptosis in favor of survival. The ubiquitin-proteasome system (UPS) is a critical cellular machinery that controls the Bcl-2 levels through regulation of protein stability. This review delves into the intricate interplay between the proteasome and Bcl-2 family members, exploring how proteasome-mediated degradation impacts cell survival and proliferation to influence cancer progression. We discuss the therapeutic potential of targeting the proteasome-Bcl-2 axis, including the use of proteasome inhibitors as anticancer agents. We examine their mechanisms of action, clinical efficacy, and limitations while exploring emerging strategies to overcome these challenges.

The advent of immune checkpoint inhibitors has introduced innovative therapeutic paradigms for the management of human epidermal growth factor receptor 2 (HER2)-negative advanced gastric or gastroesophageal junction cancer (GC/GEJC). However, the efficacy and safety of programmed cell death protein 1 (PD-1) inhibitors combined with chemotherapy versus chemotherapy alone in patients with HER2-negative advanced GC/GEJC remain contentious. The comparability among different subgroups is not fully understood, necessitating the identification of optimal patient demographics and the exploration of potential biomarkers.

The emergence of immune checkpoint inhibitors (ICIs) have provided a new perspective for cancer immunotherapy. Immune checkpoint inhibitors significantly improve the survival prognosis of patients with various advanced cancers by inhibiting immune checkpoint molecules, thereby releasing the suppression of T cells by tumor microenvironment, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1). Immune checkpoint inhibitor (ICI) therapy, while effective, gives rise to distinct immune-related adverse events (irAEs), including cardiovascular toxicities, necessitating focused research efforts to better understand and address these specific complications. The myocarditis-associated toxicity has been extensively studied. This article reviews the latest clinical and preclinical literature on the epidemiology and pathogenesis of ICI-related atherosclerosis, explores the pathophysiological mechanisms by which ICIs promote atherosclerosis, and discusses risk assessment, identification and monitoring methods, and intervention strategies for ICI treatment related atherosclerosis.

Breast cancer is the most common cancer and the main cause of death because of malignant tumors in women, worldwide. The impact of Crocus sativus on several cancers has been discussed. Recent studies provide evidence regarding the anticancer properties of C. sativus and its bioactive constituents against breast cancer. This study aims to systematically review the efficacy of this botanical drug and its constituents on breast cancer, and their mechanism of action for the first time. Due to the lack of human studies in this field, the present research focused on preclinical studies.

Epithelial ovarian cancer (EOC), accounting for 90-95% of all ovarian cancer (OC) cases, is the most lethal gynaecological malignancy, primarily due to late-stage diagnosis and the development of chemoresistance. While initial responses to Platinum- and Taxane-based chemotherapy are favorable, nearly 70% of patients relapse within five years. Although signaling pathways such as PI3K/AKT, MAPK, NF-κB, Notch, and Wnt/β-catenin have been individually studied in the context of chemoresistance, recent evidence highlights the importance of dynamic feedback loops and crosstalk among these networks in sustaining the resistant phenotype. Moreover, dysregulated microRNAs (miRNAs), as post-transcriptional regulators, fine-tune these pathways, creating self-sustaining circuits that promote drug efflux, inhibit apoptosis, and maintain cancer stemness. Reciprocal regulation between miRNAs and signaling components establishes robust networks that amplify chemoresistant phenotypes. The review provides a comprehensive overview of the molecular mechanisms driving chemoresistance, emphasising critical elements of signalling pathways and associated miRNAs that contribute to resistance and may function as biomarkers or therapeutic targets to mitigate chemoresistance. To improve clinical outcomes, future research should focus on identifying resistance-associated miRNA signatures and targeting nodal points within miRNA-signaling networks, thereby enabling the development of personalized therapies to overcome drug resistance in EOC.

Doxorubicin is a commonly used antitumor drug for the treatment of various cancers. However, its clinical application is greatly restricted by its severe cardiotoxicity. At present, doxorubicin-induced cardiotoxicity is categorized into acute and chronic forms, depending on the dosage and duration of exposure, which may eventually lead to the occurrence of heart failure. The pathogenesis of doxorubicin cardiotoxicity is associated with oxidative stress, mitochondrial damage, calcium overload, dysregulation of autophagy, and apoptosis. In forensic medical practice, cases of poisoning or even cardiac death caused by doxorubicin showed no obvious changes in cardiac morphology through routine forensic pathological examinations. The paper aims to summarize the research on the mechanisms of action of doxorubicin-induced cardiotoxicity in recent years, analyze and discuss the possible pathways of cardiomyocyte injury caused by doxorubicin, and provide references for research on the mechanisms of doxorubicin-induced cardiotoxicity and forensic application.

Liver cancer is the sixth most common cancer and the third leading cause of cancer death worldwide. The predominant type of primary liver cancer is hepatocellular carcinoma (HCC). Tumor vascular endothelial cells (VECs), a major component of cells in the microenvironment of HCC, play multifaceted roles in contributing to tumor angiogenesis, proliferation, and migration, as well as therapeutic resistance by attracting myeloid-derived suppressor cells and suppressing cytotoxic CD8 T cell differentiation and function. Recently, Wu et al reported that apatinib, an inhibitor of vascular endothelial growth factor receptor 2, can inhibit tumor VEC glycolysis by regulating phosphatidylinositol 3-kinase/protein kinase B/6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 signaling pathway to suppress HCC progression. With great interest, this editorial paper aims to review the function and key molecular signaling pathways of tumor VECs in HCC initiation and progression and summarize potential treatment options in clinical trials.

Despite the significant antitumor potential of doxorubicin and its widespread use in the treatment of various oncological diseases, its application is associated with side effects, among which the most common are cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, and gonadotoxicity. In contemporary times, innovative strategies to overcome the toxicity of doxorubicin and improve the effectiveness of therapies are intensively researched. The aim of this review is to discuss different approaches to alleviate the common toxic effects of doxorubicin, with an emphasis on oxidative stress. In particular, the review analyzes the significance of pharmaceutical nanotechnology for reducing doxorubicin toxicity while maintaining its antitumor effect (e.g., encapsulation of doxorubicin in passively and/or actively targeted nanoparticles to tumor tissue and cells). Other strategies commented in the review are the simultaneous delivery of doxorubicin with antioxidants and the administration of its derivatives with lower toxicity.

Phthalocyanines (Pcs) are well-established photosensitizers in photodynamic therapy, valued for their strong light absorption, high singlet oxygen generation, and photostability. Recent advances have focused on covalently conjugating Pcs, particularly zinc phthalocyanines (ZnPcs), with a wide range of small bioactive molecules to improve selectivity, efficacy, and multifunctionality. These conjugates combine light-activated reactive oxygen species (ROS) production with targeted delivery and controlled release, offering enhanced treatment precision and reduced off-target toxicity. Chemotherapeutic agent conjugates, including those with erlotinib, doxorubicin, tamoxifen, and camptothecin, demonstrate receptor-mediated uptake, pH-responsive release, and synergistic anticancer effects, even overcoming multidrug resistance. Beyond oncology, ZnPc conjugates with antibiotics, anti-inflammatory drugs, antiparasitics, and antidepressants extend photodynamic therapy's scope to antimicrobial and site-specific therapies. Targeting moieties such as folic acid, biotin, arginylglycylaspartic acid (RGD) and epidermal growth factor (EGF) peptides, carbohydrates, and amino acids have been employed to exploit overexpressed receptors in tumors, enhancing cellular uptake and tumor accumulation. Fluorescent dye and porphyrinoid conjugates further enrich these systems by enabling imaging-guided therapy, efficient energy transfer, and dual-mode activation through pH or enzyme-sensitive linkers. Despite these promising strategies, key challenges remain, including aggregation-induced quenching, poor aqueous solubility, synthetic complexity, and interference with ROS generation. In this review, the examples of Pc-based conjugates were described with particular interest on the synthetic procedures and optical properties of targeted compounds.

Cancer is one of the most lethal diseases of this century. Unfortunately, many anticancer agents have harsh side effects or fail to work against cancer any longer due to tolerance. Dihydropyrimidinones are promising structures containing a pyrimidine ring. Targeting Eg5 is their most well-known activity. Inhibition of this enzyme gives them the privilege of strong cytotoxic activity with less side effects. Phenyl ring is a group that can be found in the majority of organic molecules and possesses preferable pharmacokinetic and pharmacodynamic characteristics. This review studies DHPM derivatives that are substituted with a phenyl ring and possess antiproliferative ability by inhibiting Eg5. The compounds are able to inhibit different cancer cell lines, and some are more potent than the standard drug. The biological results are in accordance with the docking studies.

Nanoparticles (NPs) synthesised through biogenic routes have emerged as a sustainable and innovative platform for biomedical applications such as antibacterial, anticancer, antiviral, anti-inflammatory, drug delivery, wound healing, and imaging diagnostics. Among these, silver nanoparticles (AgNPs) have attracted significant attention due to their unique physicochemical properties and therapeutic potential. This review examines the biogenic synthesis of AgNPs, focusing on microbial, plant-based, and biomolecule-assisted approaches. It highlights how reaction conditions, such as pH, temperature, and media composition, influence nanoparticle size, shape, and functionality. Particular emphasis is placed on microbial synthesis for its eco-friendly and scalable nature. The mechanisms of AgNP formation and their structural impact on biomedical performance are discussed. Key applications are examined including antimicrobial therapies, cancer treatment, drug delivery, and theranostics. Finally, the review addresses current challenges, such as reproducibility, scalability, morphological control, and biosafety, and outlines future directions for engineering AgNPs with tailored properties, paving the way for sustainable and effective next-generation biomedical solutions.

Microtubules play a key role in cell division and cell migration. Thus, microtubule-targeting agents (MTAs) are pivotal in cancer therapy due to their ability to disrupt cell division microtubule dynamics. Traditionally divided into stabilizers and destabilizers, MTAs are increasingly being repurposed for central nervous system (CNS) applications, including brain malignancies such as gliomas and neurodegenerative diseases like Alzheimer's and Parkinson's. Microtubule-stabilizing agents, such as taxanes and epothilones, promote microtubule assembly and have shown efficacy in both tumour suppression and neuronal repair, though their CNS use is hindered by blood-brain barrier (BBB) permeability and neurotoxicity. Destabilizing agents, including colchicine-site and vinca domain binders, offer potent anticancer effects but pose greater risks for neuronal toxicity. This review highlights the mapping of nine distinct tubulin binding pockets-including classical (taxane, vinca, colchicine) and emerging (tumabulin, pironetin) sites-that offer new pharmacological entry points. We summarize the recent advances in structural biology and drug design, enabling MTAs to move beyond anti-mitotic roles, unlocking applications in both cancer and neurodegeneration for next-generation MTAs with enhanced specificity and BBB penetration. We further discuss the therapeutic potential of combination strategies, including MTAs with radiation, histone deacetylase (HDAC) inhibitors, or antibody-drug conjugates, that show synergistic effects in glioblastoma models. Furthermore, innovative delivery systems like nanoparticles and liposomes are enhancing CNS drug delivery. Overall, MTAs continue to evolve as multifunctional tools with expanding applications across oncology and neurology, with future therapies focusing on optimizing efficacy, reducing toxicity, and overcoming therapeutic resistance in brain-related diseases.

Classical Hodgkin lymphoma (cHL) is a biologically and clinically unique malignancy characterized by rare Hodgkin and Reed-Sternberg (HRS) cells surrounded by a dense and diverse inflammatory infiltrate. These malignant cells actively reshape the tumor microenvironment (TME) through metabolic reprogramming and immune evasion strategies. This review synthesizes current knowledge on how metabolic alterations contribute to tumor survival, immune dysfunction, and therapeutic resistance in cHL. We discuss novel therapeutic approaches aimed at disrupting these processes and examine the potential of combining metabolic interventions with immune-based strategies-such as immune checkpoint inhibitors (CPIs), epigenetic modulators, bispecific antibodies, and CAR-T/CAR-NK cell therapies-which may help overcome resistance and enhance anti-tumor responses. Several agents are currently under investigation for their ability to modulate immune cell metabolism and restore effective immune surveillance. Altogether, targeting metabolic vulnerabilities within both tumor and immune compartments offers a promising, multifaceted strategy to improve clinical outcomes in patients with relapsed or refractory cHL.

Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour-stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour-microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC.

Natural compounds, particularly flavonoids, have emerged as promising anticancer agents due to their various biological activities and no or negligible toxicity towards healthy tissues. Among these, isorhamnetin, a methylated flavonoid, has gained significant attention for its potential to target multiple cancer hallmarks. This review comprehensively explores the mechanisms by which isorhamnetin exerts its anticancer effects, including cell cycle regulation, apoptosis, suppression of metastasis and angiogenesis, and modulation of oxidative stress and inflammation. Notably, isorhamnetin arrests cancer cell proliferation by regulating cyclins, and CDKs induce apoptosis via caspase activation and mitochondrial dysfunction. It inhibits metastatic progression by downregulating MMPs, VEGF, and epithelial-mesenchymal transition (EMT) markers. Furthermore, its antioxidant and anti-inflammatory properties mitigate reactive oxygen species (ROS) and pro-inflammatory cytokines, restricting cancer progression and modulating tumor microenvironments. Combining isorhamnetin with other treatments was also discussed to overcome multidrug resistance. Importantly, this review integrates the recent literature (2022-2024) and highlights isorhamnetin's roles in modulating cancer-specific signaling pathways, immune evasion, tumor microenvironment dynamics, and combination therapies. We also discuss nanoformulation-based strategies that significantly enhance isorhamnetin's delivery and bioavailability. This positions isorhamnetin as a promising adjunct in modern oncology, capable of improving therapeutic outcomes when used alone or in synergy with conventional treatments. The future perspectives and potential research directions were also summarized. By consolidating current knowledge and identifying critical research gaps, this review positions Isorhamnetin as a potent and versatile candidate in modern oncology, offering a pathway toward safer and more effective cancer treatment strategies.