Multispecific antibodies (MsAbs), capable of targeting multiple antigens simultaneously, are regarded as the 2.0 version of monoclonal antibodies (mAbs), providing therapeutic benefits that significantly exceed those of mAbs. This enhanced functionality makes MsAbs a particularly promising strategy for treating solid tumors. In this comprehensive review, we summarize diverse targeting strategies, clinical trial outcomes, and existing hurdles, while proposing novel directions to enhance the development of MsAbs for overcoming the immunosuppressive tumor microenvironment (TME). Based on their therapeutic mechanisms, we categorize their actions into six principles: 1) blocking various oncogenic signaling pathways; 2) activating and redirecting cytotoxic immune cells toward tumor cells; 3) enhancing macrophage-mediated phagocytosis; 4) targeting immune checkpoints to alleviate immunosuppression; 5) modulating matrix components within the immunosuppressive TME; and 6) promoting immune cell infiltration and localized cytokine signaling. In addition, the integration of MsAbs with sophisticated technologies has opened new avenues for enhancing therapeutic efficacy. These approaches include antibody-degrader conjugates, chimeric antigen receptor T cell (CAR-T) therapies, antibody-oncolytic virus combinations, nanomaterial-based delivery systems, and messenger RNA (mRNA)-based technologies. Such innovative strategies highlight the transformative potential of MsAbs, positioning them at the forefront of next-generation cancer immunotherapies.

Alzheimer's disease (AD) is the predominant cause of dementia globally. This review clarifies the dual function of poly(ADP-ribose) polymerase 1 (PARP1) in AD pathogenesis, emphasizing its role in mediating parthanatos, a unique caspase-independent cell death mechanism. We analyze contemporary literature regarding PARP1 expression, parthanatos signaling, and pharmaceutical treatments in AD models. In addition, PARP1 exhibits context-dependent duality: its physiological nuclear expression in hippocampus neurons is essential for memory consolidation and decreases early in cognitive impairment, suggesting a correlative association with synaptic malfunction. In contrast, overactivity of PARP1 resulting from Aβ-induced oxidative stress and DNA damage induces neurodegeneration via multiple pathways, including NAD+/ATP exhaustion leading to metabolism collapse, creation of the AIF-MIF complex promoting parthanatos, NF-κB-induced neuroinflammation, dysregulation of mitophagy, and disruption of the neuroprotective SIRT1 signaling pathway. The overactivity contributes to a positive feedback loop, where PARP1 intensifies Aβ and tau protein accumulation while simultaneously disrupting the BBB. In preclinical models of AD, genetic knockout, pharmacologic agents such as PJ34 and MC2050, or precursors of NAD+ such as nicotinamide and NMN attenuate Aβ deposition, normalize metabolism, and ameliorate cognitive decline. The PARP1/parthanatos pathway is at the center of the confluence of oxidative stress, DNA damage, metabolism disorder, and neuroinflammation in AD. Metformin and other PARP1 inhibitors offer intriguing treatment options. PARP1's cell-type- and intracellular location-dependent activity necessitates careful consideration of context, dose, and disease stage while developing therapies. The present understanding in this review could inform future research on PARP1 regulation in AD clinical practice.

Immune checkpoint inhibitors (ICIs) benefit patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer (CRC), but efficacy remains limited in proficient mismatch repair/microsatellite-stable (pMMR/MSS) tumors. This review evaluates how the gut microbiota and microbial metabolites influence CRC development, the tumor microenvironment, and immunotherapy responses, with emphasis on strategies for pMMR/MSS CRC.

Colorectal cancer (CRC) represents one of the most prevalent and lethal malignancies worldwide, with rapidly increasing global incidence and mortality. Current clinical therapies for CRC are severely compromised by tumor metastasis, intrinsic and acquired drug resistance, and unsatisfactory prognosis for advanced patients, highlighting an urgent demand for novel and effective therapeutic candidates. As privileged multifunctional scaffolds, indole hybrids integrate diverse pharmacophores to achieve simultaneous modulation of multiple CRC-associated oncogenic signaling pathways and mutant proteins, enabling them to overcome the limitations of traditional single-target drugs, reduce systemic toxicity, and optimize pharmacokinetic performance. This review comprehensively summarizes the research progress of novel indole hybrids for anti-CRC therapy reported since 2021, excluding indole-pyrimidine and indole-pyridine hybrids covered in previous studies. Notably, among all summarized subclasses, indole-chalcone/chromene, indole-hydroxamic acid/benzamide, and indole-azole hybrids, show the most prominent and promising therapeutic outcomes. These three dominant hybrid categories display potent antiproliferative activity against both drug-sensitive and drug-resistant CRC cell lines, exert robust in vivo tumor growth inhibition in xenograft models, and possess favorable safety profiles with low cytotoxicity to normal cells. We systematically elaborate their key structure-activity relationships, core anti-CRC molecular mechanisms, including cell cycle arrest, apoptosis induction, and targeted pathway regulation, as well as superior preclinical pharmacological characteristics. Furthermore, the current challenges and future research directions for indole hybrid-based anti-CRC drug development are discussed.

Methotrexate is a highly effective anti-folate drug, used for a range of oncological and inflammatory conditions. Toxic effects of methotrexate on the bone marrow, mucosa, liver and kidneys are widely appreciated; however, clinicians may be less familiar with neurotoxic side-effects. Neurotoxicity is primarily reported in those receiving high-dose or intrathecal methotrexate; however, it may occur in patients receiving low-dose treatment. Symptoms range from acute headache/somnolence, sub-acute onset of seizures/stroke-like symptoms, to long-term cognitive and behavioural difficulties. Stroke-like symptoms occur several days after administration when the patient may be out of the hospital, meaning that acute care providers must be able to recognise and appropriately manage these conditions. The mechanism by which methotrexate causes neurotoxicity remains poorly understood, and although some treatments and preventative agents have been identified, they lack robust evidence at present, representing a key area for future research. This article aims to provide a state-of-the-art review of methotrexate neurotoxicity, which will increase physician awareness of this condition, its presentation, and to highlight evidence and research gaps relating to treatment and prevention.

The advent of immunotherapy, and particularly the development of immune checkpoint inhibitors (ICIs), has revolutionized the landscape of breast cancer treatment, especially for triple-negative breast cancer. However, some patients still do not benefit from immunotherapy. Breast cancer is inherently an immunotherapy "cold" tumor, which results in suboptimal clinical outcomes when ICIs are used as monotherapy. Identifying additional immunotherapeutic targets and drugs, along with developing novel strategies for combination therapy, is crucial for addressing the challenges posed by immunotherapy resistance and tumor immune escape driven by multiple mechanisms. For instance, the combination of the programmed cell death protein 1 inhibitor, pembrolizumab, with chemotherapy has demonstrated remarkable clinical efficacy and is now the preferred first-line treatment for neoadjuvant, adjuvant, and metastatic breast cancer. This review discusses recently developed ICIs and focuses on strategies combining ICIs with chemotherapy, targeted therapy, nanotherapy, and other approaches in breast cancer. This review aims to summarize recent advances in immune checkpoint inhibitor-based combination strategies in breast cancer and to provide insights into improving therapeutic efficacy, overcoming treatment resistance, and ultimately enhancing patient outcomes.

Patients with cancer cachexia have shorter survival, decreased response to therapy, functional decline, and poorer quality of life. Optimal nutritional care consists of a multimodal approach, including screening, dietary counselling, nutritional supplementation, exercise advice, and consideration of prescribable medications. The aim of this article is to review the recent evidence supporting prescribing options in cancer malnutrition and cachexia.

Significant advances in the treatment of localized gastric cancer have been achieved through early screening, improved diagnostic techniques, surgeries, and adjuvant chemotherapy; however, the need for personalized treatment remains under debate. This review highlights the use of gastric cancer organoid (GCO) models to study cancer mechanisms, drug discovery, and precision medicine, focusing on their ability to simulate the tumor microenvironment, reveal cell heterogeneity, and assess drug responses. In particular, the integration of CRISPR/Cas9 gene editing with GCOs provides a powerful platforms for identifying new drug targets and supporting clinical applications in precision medicine. This review also explores the potential of these organoids in future research, particularly in optimizing treatment strategies and developing personalized therapies, thus offering new directions for precision treatment of gastric cancer.

High-risk and relapsed/refractory (R/R) acute lymphoblastic leukemia poses significant therapeutic challenges due to emergent drug resistance and dose-limiting toxicities. Natural products, with their diverse chemical structures and pharmacological activities, provide a promising avenue for multi-target therapies.

Sulfonamides are privileged structural motifs widely found in bioactive molecules and pharmaceuticals, and their derivatives exhibit excellent structural diversity, a feature proven useful for discovering novel therapeutic agents. The development of novel sulfonamide-containing compounds with reduced toxicity, low production costs, and high potency constitutes a research focus in medicinal chemistry. Recent advances in sulfur dioxide insertion, reactions of sulfinate salts, transformation of thiols/disulfides, and sulfonyl precursor coupling have enabled efficient, green, and functional-group-tolerant synthesis of diverse sulfonamides. Moreover, the biological applications and structure-activity relationships of sulfonamides are comprehensively reviewed, including anti-diabetic, antimicrobial, anti-inflammatory, carbonic anhydrase inhibitory, anticancer, and anti-Alzheimer's disease activities, highlighting their critical roles in medicinal chemistry and drug development. In addition, FDA-approved drugs bearing the sulfonamide moiety over the past 50 years are also summarized. It is anticipated that this review will provide medicinal chemists with clear insights for the structural design and development of low-toxicity, high-potency sulfonamide-based drugs targeting numerous life-threatening diseases.

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy often diagnosed at an advanced stage. For over a decade, gemcitabine-cisplatin (GemCis) remained the standard of care with limited survival benefit. The advent of immune checkpoint inhibitors (ICIs) has transformed the therapeutic landscape, but variability in outcomes and a rapidly expanding evidence base require systematic synthesis.

Antibiotics are among the transformative advances in medicine, but many interact with mammalian cellular targets and pathways beyond their antimicrobial activity. A clinically important expression of these off-target effects is hematologic toxicity, including immune-mediated cytopenias and direct bone marrow suppression. This narrative review examines whether the same biology that injures normal hematopoietic cells can, in selected contexts, reveal therapeutically exploitable vulnerabilities in leukemia. We synthesize molecular, clinical, and preclinical evidence and organize it into an integrative framework linking mitochondrial translation inhibition, mitonuclear imbalance, oxidative phosphorylation failure, reactive oxygen species generation, DNA/topoisomerase stress, autophagy and lysosomal-flux blockade, and apoptosis modulation with both hematotoxicity and antileukemic activity. The strongest preclinical evidence supports selected tetracyclines, macrolides, and oxazolidinones, whereas evidence for beta-lactams, glycopeptides, polymyxins, rifamycins, fluoroquinolones, and folate-pathway agents remains more limited or largely hypothesis-generating. Importantly, antibiotic-induced cytopenia should not be interpreted as proof of leukemia selectivity: immune-mediated toxicity, supratherapeutic in vitro exposure, normal progenitor injury, pharmacokinetic constraints, microbiome effects, and resistance mechanisms all narrow the translational window. Overall, antibiotic hematotoxicity is best viewed as a biologically informative signal that can guide mechanism-based repurposing and combination strategies, but clinical development requires rigorous pharmacokinetic/pharmacodynamic validation, normal hematopoietic comparators, and biomarker-driven patient selection.

Pharmacodynamic analyses are increasingly important to early-phase oncology drug development, however these analyses use invasive methods to collect patient material. Yet, their role in guiding recommended phase II dose (RP2D) decisions remains unclear. Therefore, this review evaluates how pharmacodynamic analyses assisted the determination of the recommended phase II dose (RP2D) in first-in-human cancer trials of small-molecule agents.

Cancer immunotherapy enhances the body's ability to recognize and eliminate tumor cells, mainly by modulating immune checkpoints such as PD-1/PD-L1 and CTLA-4. Monoclonal antibody inhibitors targeting PD-1 or PD-L1 have transformed cancer care, but their high cost, IV administration, and immune-related toxicities have encouraged the development of small-molecule alternatives. Early PD-L1 small-molecule inhibitors, pioneered by Bristol Myers Squibb, block PD-1/PD-L1 interactions by occupying hydrophobic pockets on PD-L1, and SAR studies continue to refine their potency and selectivity. This review focuses on how the structural scaffolds of small-molecule PD-L1 inhibitors determine their mechanisms of action, protein interactions, and biological performance. We examine how different chemotypes influence dimerization of PD-L1, disruption of PD-1 binding, or engagement of additional immune-modulatory pathways. Special attention is given to scaffolds capable of acting through more than one mechanism, as these may offer broader or more durable immunomodulatory effects. We also compare how scaffold design correlates with activity across in vitro assays, co-culture immune models, and in vivo tumor systems, highlighting the physicochemical features that enable or limit translatability. Finally, we discuss emerging clinical efforts, the challenges underlying trial failures, and how refined structural design may guide the next generation of small-molecule PD-L1 inhibitors.

Pancreatic cancer is a highly lethal gastrointestinal malignancy with chemotherapy resistance as a major obstacle to improving prognosis. Emerging evidence indicates that the intratumoral microbiome is closely implicated in the development, progression, and therapeutic response of pancreatic cancer. The intratumoral microbiome of pancreatic cancer is mainly composed of Proteobacteria and Firmicutes, and its composition is significantly correlated with patient survival. Intratumoral microbes drive tumor progression by remodeling the immune microenvironment, inducing DNA damage, and activating oncogenic signaling pathways. Meanwhile, they exacerbate chemotherapy resistance via multiple mechanisms, including remodeling the extracellular matrix, establishing an immunosuppressive microenvironment, and metabolically inactivating chemotherapeutic agents. This review systematically summarizes the community composition of the intratumoral microbiome in pancreatic cancer, its regulatory effects, and underlying mechanisms on chemotherapy resistance, as well as the latest advances in targeted therapeutic strategies.

Cancer represents a major global health threat, and the development of effective anticancer therapies is urgently needed. Sanguisorba officinalis (DY), a traditional Chinese herbal medicine, possesses properties including cooling blood and promoting blood circulation, detoxifying pathogenic toxins, and astringing sores. Increasing evidence suggests that DY and its bioactive constituents exhibit notable anti-tumor effects, with mechanisms that align with traditional Chinese medical principles of enhancing Zhengqi (fuzheng) and removing Xieqi (quxie). However, a comprehensive review that systematically summarizes the antitumor potential of DY and its bioactive constituents is still lacking. In this review, we summarize the anticancer effects of DY extracts and Ziyuglycosides. In vitro studies demonstrate that DY and its active components can inhibit tumor cell proliferation, induce cell cycle arrest, trigger mitochondria-mediated apoptosis, enhance autophagic flux, and suppress invasion and metastasis by regulating Wnt/β-catenin, PI3K/AKT/mTOR, MAPK, and EGFR/NF-κB signaling pathways, as well as downregulating epithelial-mesenchymal transition-related transcription factors and matrix metalloproteinases. In vivo studies confirms DY and its active components inhibit tumor growth and metastasis, regulate the tumor immune microenvironment, modulate Th17/Treg balance, activate CD8+ T cells, and enhance the anti-tumor immune responses. Notably, clinical application evidence indicates that Diyu Shengbai Pian, a preparation derived from DY, have been proven effective in alleviating leukopenia caused by chemotherapy or radiotherapy, highlighting DY's dual therapeutic potential in tumor suppression and mitigating treatment-related adverse reactions. However, current research mainly focuses on in vitro cellular studies and in vivo animal models, lacking large-scale, standardized clinical trials to validate its long-term efficacy and safety in humans. This review systematically summarizes the mechanisms of the anti-tumor and immunomodulatory effects of DY and its active components, and outlines advancements in improving their in vivo delivery efficiency, providing a theoretical basis and research reference for the translational application of DY in cancer therapy.

Choroidal neovascularization (CNV) is a major pathological hallmark of fundus diseases, such as age-related macular degeneration, and is commonly treated with anti-vascular endothelial growth factor (VEGF) agents. However, resistance to or a suboptimal response to anti-VEGF therapy, particularly in arteriolar CNV, remains a significant clinical challenge. Arteriolar CNV, characterized by arterialized vessels, feeding arterioles with high blood flow, and prominent fibrosis, remains persistently active and responds poorly to standard anti-VEGF therapy. Notch signaling confers anti VEGF resistance in various diseases including cancer and corneal neovascularization. However, its role in anti-VEGF resistant arteriolar CNV has not been systematically summarized. This review highlights Notch signaling as a key regulator of both physiological and pathological arterial remodeling, driving arteriolar differentiation and contributing to resistance to VEGF inhibitors. In tumors, Notch signaling plays a crucial role in driving arteriolar neovessel formation, promoting macrophage-mediated vascular remodeling, and enhancing fibrosis, all of which contribute to anti-VEGF resistance. We also discuss whether and how similar mechanisms may operate in arteriolar CNV and proposes that Notch signaling represents a potential therapeutic target. Furthermore,combining Notch inhibitors with anti-VEGF therapy may improve outcomes in patients with arteriolar CNV resistant to anti-VEGF therapy, thereby providing a potential therapeutic strategies. Future studies are warranted to elucidate the specific roles of Notch signaling in CNV and optimize therapeutic strategies for improved safety and efficacy.

Acyl hydrazones and hydrazides are of great interest in medicinal chemistry because their pharmacophoric group (-CO-NH-N=CH-) shows keto-enol tautomerism and E/Z isomerism, which gives them dynamic stereochemical properties. They are of particular value to medicinal chemists due to their ability to undergo multiple weak non-covalent interactions and metal chelation. This review systematically studied the various biological activities of acyl hydrazone and hydrazide derivatives, which are therapeutically important compounds. Although several synthetic methods, including microwave-assisted, ultrasound-assisted, aqueous-phase, and enzyme-catalyzedare mentioned, the main emphasis is to gain insight into the pharmacological significance and bioactivity of these derivatives. It also found that the structure-activity relationships (SAR) influence their pharmacologic outcomes. Improved synthetic accessibility, combined with their potential to interact with multiple biological targets, highlights the value of acyl hydrazones as versatile candidates in therapeutic research. These features collectively support their continued investigation as important molecular frameworks for the design and development of novel bioactive agents.

Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need for improved targeted therapies amid a rising global and Indian cancer burden. This comprehensive review critically summarizes advances from 2021-2025 in the design of selective PI3K inhibitors based on the 1,3,5-triazine (s-triazine) scaffold, emphasizing how its symmetric 2/4/6 substitution vectors, electron-deficient hinge-binding profile, and modular cyanuric chloride - enabled SNAr synthesis accelerate structure - activity relationship (SAR) optimization. Medicinal chemistry and biological evidence across multiple triazine chemotypes (benzoyl-hydrazide, thiophene/thiophenyl-arylurea, aminopyrimidine, dimorpholinyl, benzimidazole, phenylamino, and pyrazolyl derivatives) reveal convergent design rules: heteroaryl/aminopyrimidine hinge binders, pocket-filling hydrophobic arms, and solvent-exposed polar groups (notably morpholine/dimorpholine or sulfonyl piperazine) collectively improve potency, isoform selectivity, and cellular efficacy. Mechanistically, representative compounds induce G0/G1 arrest and apoptosis with suppression of p-PI3K/p-AKT and downstream markers, supported by docking/MD interactions frequently involving Val851 (hinge), Asp810, Lys802, and Gln859. Despite substantial progress, pharmacokinetic liabilities, resistance pathways, and isoform-associated adverse effects remain key barriers to translation. Future development should prioritize rational isoform targeting, hybrid/multitarget designs, systematic ADME refinement, and AI-driven SAR modeling to advance s-triazine PI3K inhibitors toward clinically feasible cancer therapeutics.

Ovarian cancer remains one of the most frequently diagnosed and lethal gynaecological malignancies. Standard treatment involves surgical cytoreduction followed by chemotherapy based on platinum compounds and taxanes. Despite initial therapeutic efficacy, many patients experience disease recurrence and develop drug resistance, posing a significant clinical challenge. This review summarises the main molecular mechanisms underlying resistance to commonly used drugs, including paclitaxel, cisplatin, and PARP inhibitors. The role of multidrug resistance (MDR), associated with the overexpression of ABC transporters and alterations in drug metabolism, is discussed. Particular attention is given to cellular mechanisms, including changes in microtubule structure, regulation of apoptosis, and activation of signalling pathways such as PI3K/AKT/mTOR. Mechanisms related to drug transport, detoxification, and DNA repair are also addressed, together with the influence of the tumour microenvironment and epigenetic modifications. Understanding these mechanisms may contribute to the development of novel therapeutic strategies.