L-asparaginase (L-ASNase) is a key therapeutic enzyme used in the treatment of acute lymphoblastic leukemia and other hematological malignancies. However, its clinical application is limited by a short plasma half-life, significant toxicity, and immunogenicity. To address these limitations, various strategies have been developed, including conjugation of the enzyme with polyethylene glycol and the use of enzymes from alternative sources with lower immunogenicity. Nevertheless, effective targeting of tumor cells, particularly in solid tumors, remains a major challenge. Protein fusion technology has emerged as a promising approach to improve the pharmacological properties of L-asparaginase by enhancing stability, prolonging circulation time, enabling targeted delivery, and integrating multiple functional domains into a single construct, thereby addressing several limitations simultaneously. This review analyzes current strategies for the design of L-asparaginase-based fusion proteins, including the fusion of protein domains to improve pharmacokinetics and the fusion of targeting peptides or proteins to enhance local cytotoxicity. A comparative analysis indicates that elastin-like peptide (ELP)-based constructs primarily enhance the half-life of L-ASNase, whereas albumin-binding domain (ABD)- and heparin-binding domain (HBD)-based fusions provide more pronounced improvements in both half-life extension and in vivo efficacy. However, described strategies require further validation to ensure enhanced selectivity. Overall, fusion protein technology represents a promising avenue for the development of next-generation L-asparaginase therapeutics.

Cellular and immunological cancer therapies have substantially changed the treatment landscape of malignant diseases. In particular, chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitors (CPI) have enabled durable responses in previously refractory malignancies. However, these treatment strategies are associated with distinct immune-mediated toxicities that differ considerably from the toxicity profiles observed with conventional cytotoxic chemotherapy. Hematologic complications represent an important subgroup of these adverse events. Hematologic immune-related adverse events (irAEs) under CPI therapy are rare but may be associated with considerable morbidity and mortality. In contrast, hematologic toxicities are common after CAR T-cell therapy and are summarized under the term ICAHT (immune effector cell-associated hematotoxicity). These cytopenias may present early after therapy due to lymphodepleting conditioning or later as prolonged or biphasic cytopenias associated with inflammatory bone marrow suppression. In addition, severe hyperinflammatory syndromes such as immune effector cell-associated hemophagocytic syndrome (IEC-HS) may occur and require rapid recognition and treatment. A structured diagnostic approach is essential to differentiate therapy-related cytopenias from disease progression, bone marrow infiltration, or secondary hematologic malignancies. Management strategies depend on the severity of the cytopenia and include supportive measures, immunomodulatory therapies, and in selected cases targeted anti-cytokine treatments. Early recognition and interdisciplinary management are crucial to reduce morbidity and improve patient outcomes.

Immune checkpoint inhibitors (ICIs), particularly antibodies targeting PD-1, PD-L1, and CTLA-4, have fundamentally transformed the treatment landscape of numerous malignant diseases. By blocking T-cell inhibitory mechanisms, they enable an enhanced immune response against malignancies, but can also trigger immune-related adverse events (irAEs). Pulmonary irAEs - most notably ICI-associated pneumonitis (ICI-P) - occur in up to 20% of treated patients (with study-reported rates ranging from 1-6%) and may progress to respiratory failure. The clinical presentation is characterized by dyspnea, cough, and hypoxemia; radiologically, organizing pneumonia, NSIP pattern, and bronchiolocentric pattern are most commonly observed. Management is severity-dependent and includes treatment interruption, immunosuppression with corticosteroids, and, where necessary, second-line immunosuppressive therapy. The most important differential diagnoses include infection, tumour progression, and radiation pneumonitis.

Immunotherapies, including checkpoint inhibitors and T-cell-activating therapies (CAR-T cells, BiTE), have transformed oncology but carry risks of severe toxicities. Checkpoint inhibitors may induce immune-related adverse events (irAEs) such as pneumonitis, myocarditis, or neurological syndromes, often requiring intensive care. T-cell therapies frequently cause acute cytokine release syndrome (CRS) and neurotoxicity (ICANS), while late toxicities like hemophagocytic syndrome (IEC-HS) and delayed neurotoxicity (TIAN, Guillain-Barré) are gaining relevance. Management includes grade-adapted immunosuppression, steroids, IL-6/IL-1 inhibitors, and interdisciplinary intensive care. Despite established algorithms, prognosis remains critical in multiorgan involvement or other high-grade toxicities. Early diagnosis and individualized risk-benefit assessment are crucial for treatment success.

Cancer immunotherapies, particularly immune checkpoint inhibitors (ICIs), have proven to be a very effective and well-established type of therapy for advanced malignancies. Although generally considered well tolerated, immune-related adverse events, which can sometimes be severe, do occur. Unlike other types of adverse events, immune-mediated renal toxicity is rare and can occur after significant delay. Diagnosing immune-mediated renal toxicity can often be difficult, due to possible alternative causes of acute kidney injury, especially in this particular patient population. Acute interstitial nephritis is the most common finding in kidney biopsies. In most cases, ICI-mediated nephritis can be treated effectively by discontinuing ICI therapy and initiating corticosteroid therapy. Renal outcomes are generally favorable. Other types of targeted immunotherapy, such as CAR-T-cell or BiTE therapies play a minor role in renal toxicity. However, due to their increase in usage, possible renal adverse effects of these therapies should receive greater attention.

Immune-mediated adverse effects are becoming increasingly common due to the now widespread use of immune checkpoint inhibitor (ICI) therapies in oncology. The gastrointestinal tract and liver are among the most frequently affected sites. Common manifestations include diarrhea, enterocolitis and hepatitis, while gastritis, duodenitis, cholangitis and pancreatitis are less common. Prompt diagnostic evaluation is essential and includes exclusion of infectious causes, stage-based severity classification, endoscopic evaluation for gastrointestinal symptoms, and close laboratory monitoring for hepatic involvement. Histological confirmation should be performed in severe cases. Management follows a stepwise approach according to severity. Mild cases can be treated symptomatically, whereas moderate to severe toxicity requires corticosteroid therapy and a temporary interruption of ICI therapy. In steroid-refractory cases, early escalation to additional immunosuppressants should be considered. Since prolonged corticosteroid exposure can worsen oncological outcomes, steroid-sparing strategies are becoming increasingly important.

Chemotherapy-related fatigue, sleep disturbance, and psychological distress significantly impair quality of life (QoL) in cancer patients. Traditional Chinese medicine (TCM) non-pharmacological therapies are increasingly used as supportive care, yet their comparative effectiveness remains unclear. This study aimed to evaluate and compare five TCM-based interventions for improving QoL and emotional well-being in chemotherapy patients.

Opioids are frequently prescribed for cancer pain management, yet accumulating evidence suggests that opioid exposure may be associated with inferior outcomes in patients also undergoing treatment with immune checkpoint inhibitors (ICIs). To synthesize mechanistic and clinical evidence linking opioids to the PD-1/PD-L1 axis, the literature was searched up to 18 January 2026, with study selection and data extraction focused on (i) cancer-cell and immune-cell effects of opioid agonism or antagonism on PD-1/PD-L1 biology, and (ii) clinical studies reporting ICI outcomes (progression-free survival, overall survival, or treatment duration) with concomitant opioid exposure. Preclinical studies support multiple, non-mutually exclusive mechanisms: opioids can induce PD-L1 in tumour cells, modulate innate-inflammatory pathways (including TLR4-linked cascades), promote dysfunctional T-cell phenotypes that reduce responsiveness to PD-1 blockade, and show context- and opioid-dependent effects. Clinical cohorts and meta-analytic datasets in non-small cell lung cancer and other tumour types report associations between opioid exposure (including higher morphine-equivalent dosing) and worse ICI outcomes. The intersection of opioid signaling with PD-1/PD-L1 biology likely operates across cancer cell-intrinsic and immune cell-intrinsic pathways, providing a mechanistic rationale for prospective evaluation of opioid-sparing strategies and/or peripheral opioid antagonism as adjuncts to checkpoint blockade.

Goniothalamin (GTN), a natural styryl-lactone from the Goniothalamus genus, has demonstrated cytotoxic properties against a variety of human cancer cell lines with minimal effects on normal cells. Its traditional medicinal use and preliminary preclinical evidence suggest potential as a selective anticancer agent. The purpose of this review is to summarize the preclinical anticancer activity, molecular mechanisms, and therapeutic potential of GTN and its semi-synthetic derivatives across cancer cell lines and animal models. A comprehensive literature search was conducted on the anticancer effects of GTN using databases including PubMed, Scopus, and ScienceDirect. Studies reporting in-vitro cytotoxicity, half-maximal inhibitory concentration (IC50) values, mechanisms of action, synergistic drug effects, and in-vivo antitumor efficacy were included. Data on GTN enantiomers and semisynthetic derivatives were also analyzed. GTN exhibited potent, dose- and time-dependent cytotoxicity in breast, colorectal, hepatoma, leukemia, and other cancer cell lines (IC50 in the low micromolar range), while sparing normal cells. Mechanistically, GTN induced DNA damage, reactive oxygen species (ROS) generation, cell cycle arrest, endoplasmic reticulum stress, apoptosis, autophagy, necroptosis, and anoikis. The anticancer activity of GTN enantiomers appears to be cell-line dependent: although the (R)-enantiomer showed higher potency in several cancer models, the (S)-enantiomer displayed greater activity in selected cancer cell lines. GTN synergized with chemotherapeutics such as paclitaxel, vinblastine, and cisplatin, enhancing apoptosis and reducing cell viability. Semi-synthetic derivatives, including methoxy- and nitro-substituted analogs, demonstrated enhanced potency and selectivity. In animal models, GTN exhibited antitumor activity without detectable toxicity. GTN is a promising natural anticancer agent with multimodal mechanisms of action and selective cytotoxicity. Semisynthetic derivatives further improve its potency and specificity. Further in-vivo studies, bioavailability, and pharmacokinetic investigations are warranted to advance GTN towards clinical application.

The cyclic GMP-AMP (cGAS) synthase and stimulator of interferon genes signaling pathway plays a central role in bridging innate and adaptive immunity, particularly within the context of cancer. Activation begins when cytosolic double-stranded DNA is detected, leading to the production of cyclic GMP-AMP (cGAMP) and subsequent activation of STING. This initiates a cascade that induces the expression of type I interferons (IFN) and proinflammatory cytokines, enhancing antitumor immune responses through the stimulation of dendritic cells, cytotoxic T lymphocytes, and natural killer cells. Despite strong therapeutic potential, many currently available cyclic dinucleotide (CDN) and synthetic noncyclic dinucleotide (non-CDN) STING agonists face critical limitations. Common issues include poor pharmacokinetics, low cellular permeability, enzymatic degradation, and inadequate systemic bioavailability. In some cases, excessive immune activation has been observed, resulting in toxicity, chronic inflammation, or immunosuppressive tumor microenvironments. Furthermore, species-specific activity restricts the translational relevance of several compounds. These limitations highlight the need for the development of novel STING agonists with improved potency, selectivity, safety, and pharmacological profiles. This review presents a detailed analysis of molecular design approaches and structure-activity relationship (SAR) data for STING agonists, emphasizing their relevance in cancer therapy. A total of 60 synthetic compounds with diverse chemical scaffolds are examined to identify structural features linked to enhanced STING activation. These findings may support the discovery of novel STING-targeted molecules that could improve therapeutic outcomes in cancer treatment.

The genus Eugenia comprises approximately 1050 species widely used in traditional medicine and human nutrition due to their diverse pharmacological properties. This review aimed to critically summarize the anticancer potential of Eugenia species and to correlate their biological activities with the presence of bioactive phytochemicals. Literature published between 2013 and 2025 was retrieved from PubMed, SciELO, and Google Scholar databases using terms related to Eugenia, cancer, antiproliferative, and cytotoxic activities. Increasing evidence has demonstrated the anticancer effects of selected Eugenia species in in silico, in vitro, and in vivo models against different cancer types. These effects are associated with multiple mechanisms, including apoptosis induction via caspase-3/7 activation and Fas receptor upregulation, inhibition of tumor cell migration and invasion through suppression of MMP-2 and MMP-9, and cell cycle arrest. The observed activities are closely related to the presence of flavonoids, phenolic acids, carotenoids, monoterpenes, triterpenes, and sesquiterpenes. Despite promising preclinical findings, limitations such as the scarcity of in vivo studies, lack of extract standardization, and absence of clinical trials still hinder the translational application of Eugenia-derived compounds in oncology. Future studies focusing on mechanistic elucidation, bioavailability, toxicity, and clinical validation are essential for the development of Eugenia-based anticancer therapies.

Chemotherapy resistance remains a major clinical challenge in the treatment of gastrointestinal (GI) cancers. Mitochondrial remodeling contributes to chemoresistance through several interconnected functional modules, including metabolic reprogramming, elevation of the apoptotic threshold, adjustment of the reactive oxygen species setpoint, and mitophagy-mediated mitochondrial quality control. Polysaccharides and polysaccharide-based systems may represent promising candidates for modulating mitochondria-associated dysfunctions because of their structural diversity, biological activity, and generally favorable biocompatibility in specific experimental settings.

Oxidative stress, resulting from the disruption of redox homeostasis, is increasingly recognized as a central driver of gastric cancer pathogenesis and a critical determinant of cell fate. An imbalance between reactive oxygen species (ROS) production and cellular antioxidant defenses leads to oxidative stress, which may ultimately result in cellular oxidative death. Helicobacter pylori (H. pylori), through its virulence factors, induces a vicious cycle of oxidative stress and inflammation that collectively remodels the tumor microenvironment. Gastric cancer is molecularly heterogeneous, and ROS demonstrate profound context dependency across these different subtypes, with distinct mechanisms governing ROS generation, antioxidant defense, and redox-regulated cell death. Importantly, ROS orchestrate a diverse repertoire of cell death modalities in gastric cancer, including ferroptosis, apoptosis, necroptosis, cuproptosis, paraptosis, pyroptosis, and oxeiptosis via a regulatory network involving key molecules such as GPX4, SLC7A11, NRF2, and caspases. In-depth research into the mechanisms of cell death holds promise for developing preventive and therapeutic agents. This review summarizes the mechanisms of ROS‑regulated cell death and explores various therapeutic strategies, including the combined use of small‑molecule compounds and emerging nanomaterial‑based approaches, alongside conventional chemotherapy, immunotherapy, and radiotherapy, to target oxidative stress. It also highlights recent advances, opportunities, and challenges in translating these strategies into gastric cancer therapy. In conclusion, this review offers a mechanistically grounded framework for developing redox-targeted precision therapies in gastric cancer.

As cancer incidence rises in Asian countries, chemotherapy remains central to treatment amid rapid population aging and declining fertility in most of them. These trends underscore concern over long-term reproductive health, as chemotherapy-induced ovarian toxicity and premature ovarian insufficiency (POI) emerge as major late effects with unclear population-specific susceptibility. This review examines chemotherapy-induced ovarian damage via the PI3K-AKT-FOXO3 signaling axis, a key regulator of follicular quiescence, stress responses, and ovarian longevity. Evidence was synthesized from human studies, experimental models, and mechanistic investigations to develop this population-specific conceptual framework. Chemotherapy initiates DNA damage and oxidative stress, which subsequently activate interconnected pathways involving mitochondrial dysfunction, dysregulated autophagy, apoptosis, ferroptosis, inflammatory signaling, and dysregulation of the PI3K-AKT-FOXO3 axis, ultimately accelerating follicular activation and depletion. A distinctive contribution of this review is the integration of longevity-associated genetic susceptibility with ovarian vulnerability, highlighting evidence suggesting that certain FOXO3 and PI3K-AKT pathway variants, reported to be more prevalent in several Asian populations, may influence susceptibility to chemotherapy-induced ovarian injury. This review proposes a two-hit hypothesis as a conceptual framework integrating currently available molecular, experimental, and population-based evidence while acknowledging that direct clinical validation remains limited. Within this framework, longevity-associated genetic predisposition affecting the PI3K-AKT-FOXO3 axis constitutes the first hit, whereas chemotherapy-induced cellular stress represents the second hit, together accelerating follicular burnout and increasing the risk of POI. This framework supports future evaluation of genotype-informed risk stratification, individualized fertility preservation strategies, and prospective validation in Asian cancer cohorts, with the ultimate goal of informing ethnicity-specific fertility preservation strategies and optimized chemotherapy protocols.

Immune checkpoint inhibitor (ICI) therapy for colorectal cancer (CRC) can be accompanied by endocrine adverse events, yet the comparative risk across commonly used regimens remains unclear. We therefore conducted a network meta-analysis of randomized controlled trials in CRC published up to November 22, 2025, estimating risk ratios (RRs) with 95% confidence intervals (CIs) and assessing risk of bias. Six RCTs were included. Relative to conventional therapy, ICI-based regimens were associated with a higher thyroid-related toxicity burden. Pembrolizumab and ICI+tyrosine kinase inhibitor (TKI) significantly increased the risk of hypothyroidism, whereas hyperthyroidism was significantly higher with ICI+TKI and ICI plus chemotherapy plus an anti-angiogenic antibody (ICI+Chem+Antiangio-Ab). Grade 1-2 adverse events were consistently increased across ICI-based treatments. For thyroiditis, diabetes mellitus, adrenal insufficiency, and grade 3-4 adverse events, effect estimates were imprecise with wide 95% CIs; nevertheless, SUCRA rankings tended to place ICI+TKI toward the higher-risk end for thyroiditis and diabetes. These findings indicate that ICI-containing strategies in CRC increase risks of endocrine adverse events-particularly for thyroid dysfunction-supporting the need for proactive endocrine monitoring and standardized management, while highlighting the limited precision of current evidence for rarer endpoints and severe toxicity.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. Immune checkpoint inhibitor (ICI) monotherapy has shown limited efficacy in PDAC, whereas the potential clinical value of first-line ICI-based combination regimens remains unclear. Through a systematic review and meta-analysis, this study aimed to evaluate the efficacy and safety of first-line ICI-based combination regimens in advanced PDAC.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapeutics yet frequently induce renal injury and multi-organ immune-related adverse events (irAEs) that present substantial clinical management challenges. Critical evidence gaps persist regarding dynamic immune microenvironment interactions and optimal organ-protective strategies.

Proliferating Cell Nuclear Antigen (PCNA) is a core protein in DNA replication and repair. Its functional dysregulation drives tumorigenesis and therapeutic resistance, making it a critical anticancer target. However, the fundamental conflict between PCNA's indispensable "guardian" function in normal cells and its hijacked "accomplice" role in cancer cells constitutes the central challenge for targeted intervention: how to eradicate tumors while avoiding severe toxicity to normal tissues. This review aims to systematically review the latest advances and translational dilemmas in the field of PCNA-targeted therapy. It outlines various intervention strategies, including small-molecule inhibitors, proteolysis-targeting chimeras, post-translational modification interference, and synthetic lethality approaches, analyzing their potential and limitations in preclinical research. The review focuses on dissecting key bottlenecks hindering clinical translation, such as the selectivity dilemma, delivery barriers, and resistance evolution. Concurrently, it critically examines how cross-disciplinary technologies-including artificial intelligence, spatiotemporal regulation, and synthetic biology-offer novel ideas to address these bottlenecks, while clarifying that most remain in early exploratory stages. By synthesizing progress, challenges, and future directions, this article provides a framework to inform the development of highly selective and translatable PCNA-based anticancer strategies.

Lung cancer in individuals who have never smoked (LCINS) represents a clinically and biologically distinct subset of non-small cell lung cancer, driven predominantly by oncogenic alterations rather than tobacco-related mutagenesis. This review aims to summarize current and emerging targeted and immune-based therapeutic strategies in LCINS individuals. These patients present a molecular profile that differs substantially from tobacco-associated disease and has direct consequences for treatment selection. Evidence published over the past five years has clarified how these molecular features shape treatment response and resistance in this setting. Particular attention is given to tumors with alterations in epidermal growth factor receptor, anaplastic lymphoma kinase, c-ros oncogene 1, rearranged during transfection, Mesenchymal-Epithelial Transition (MET) exon 14 skipping mutation, human epidermal growth factor receptor 2, valine-to-glutamic acid substitution at codon 600 of the BRAF gene (BRAF V600E), and neurotrophic tyrosine receptor kinase, which together comprise the dominant driver landscape in never-smoker lung cancer. Although third-generation tyrosine kinase inhibitors have markedly improved response rates in several of these subgroups, long-term disease control is frequently compromised by acquired resistance, and heterogeneous drug exposure, particularly in the central nervous system. By contrast, immune checkpoint inhibitors have yielded limited benefit, in keeping with the low mutational burden and generally low baseline immune activation observed in most LCINS tumors. As a result, alternative approaches such as antibody-drug conjugates, bispecific antibodies, and adoptive cellular therapies are being evaluated to address gaps left by existing treatments.

Despite the use of targeted and/or immune-based therapeutic approaches, mortality rates among melanoma patients are high, mainly due to drug-induced resistance mechanisms. In parallel, alterations of epigenetic mechanisms (e.g., deregulated patterns of DNA methylation, aberrant histone modifications and abnormal expression levels of non-coding RNAs [ncRNAs]) have been associated not only with the pathophysiology of melanoma but also with the resistance against various immunotherapeutic drugs. In this review article, we discuss the involvement of different types of epigenetic mechanisms in melanoma progression. In addition, we report on melanoma's immune environment and immunosuppressive mechanisms while we highlight the role of immune checkpoint inhibitors (ICIs) as an anti-melanoma therapeutic approach. Moreover, we describe the underlying mechanism(s) by which deregulated epigenetic patterns promote drug resistance against ICIs and how epigenetic drugs (utilized either alone or in combination with various ICIs) can reverse immune resistance. Furthermore, we discuss the major limitations and future directions towards clinical translation of epigenetic drugs, mainly in combination with ICIs. Finally, we state the potential use of emerging technologies (e.g., single-cell transcriptomics and spatial transcriptomics), along with epigenetic priming for improvement of clinical implementation and therapeutic outcomes in melanoma management.