Madangamine alkaloids have attracted considerable interest in the scientific community due to their complex polycyclic structures and potent biological activities. The six members identified to date have exhibited diverse and significant cytotoxic activities against various cancer cell lines. Despite their structural complexity, seven total syntheses-covering five of the six members-have been reported to date. These syntheses, involving 28 to 36 steps and global yields ranging from 0.006% to 0.029%, highlight the formidable challenge these compounds present. This review summarizes the key synthetic strategies developed to access critical fragments, including the construction of the ABC diazatricyclic core and the ACE ring systems. Approaches to assembling the ABCD and ABCE tetracyclic frameworks are also discussed. Finally, we highlight the completed total syntheses of madangamines A-E, with a focus on pivotal transformations and strategic innovations that have enabled progress in this field.

Microorganisms serve as a vital source of natural anticancer agents, with many of their secondary metabolites already employed in clinical oncology. In recent years, salt-adapted microbes, including halophilic and halotolerant species from marine, salt lake, and other high-salinity environments, have gained significant attention. Their unique adaptation mechanisms and diverse secondary metabolites offer promising potential for novel anticancer drug discovery. This review consolidated two decades of research alongside current global cancer statistics to evaluate the therapeutic potential of salt-adapted microorganisms. Halophilic and halotolerant species demonstrate significant promise, with their bioactive metabolites exhibiting potent inhibitory effects against major cancer cell lines, particularly in lung and breast cancer. Evidence reveals structurally unique secondary metabolites displaying enhanced cytotoxicity compared to conventional anticancer drugs. Collectively, salt-adapted microorganisms represent an underexplored yet high-value resource for novel anticancer agents, offering potential solutions to chemotherapy resistance and treatment-related toxicity.

Extensive-stage small cell lung cancer (ES-SCLC) has poor prognosis. While immune checkpoint inhibitors (ICIs) with chemotherapy show survival benefits in trials, real-world data from Asia are scarce. This study evaluates real-world efficacy and safety of chemotherapy with or without ICIs in Taiwanese patients with ES-SCLC and identifies survival predictors.

Systemic Capillary Leak Syndrome (SCLS) and Cytokine Release Syndrome (CRS) have both been described as rare but severe adverse reactions induced by Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab. We report the case of a 40-year-old woman undergoing treatment with pembrolizumab for a stage 4 cervical squamous cell carcinoma who presented with anasarca, hypotension, hemoconcentration and signs of multisystemic inflammation. After elimination of alternative causes such as nephrotic syndrome, cardiac dysfunction and cirrhosis, she was diagnosed with both pembrolizumab-induced SCLS and CRS. She was successfully treated with a multimodal treatment approach including intravenous immunoglobulins, steroids, diuretics and axitinib for SCLS as well as ruxolitinib for CRS. After several months of hospitalization, her symptoms finally improved with this treatment regimen, and she was able to attain euvolemic state and be discharged from the hospital. This case highlights certain rare and severe adverse effects of treatment with PD-1 inhibitors. Furthermore, it proposes a novel therapeutic approach for similar cases based upon probable underlying physiopathological mechanisms in SCLS and CRS.

Selective outcome-reporting bias refers to the selective reporting of a subset of study findings. This methodological limitation may occur in cancer-related acupuncture studies, where valid empirical studies on psychometric performance are still lacking. We assessed the risk of selective outcome reporting bias in studies published in English that were included in a systematic review on acupuncture for preventing cancer chemotherapy-induced nausea and vomiting. For each study, we searched for registry availability and, if present, assessed its validity. We described each study outcome (nausea, vomiting, or both) according to the following seven items: type of outcome, domain, specific measurement, specific metric, type of data, methods of aggregation, and timepoint unit and time. Eleven studies published between 1987 and 2019 in English were evaluated. Only four (36%) had a registry, of which only two were prospective and therefore considered valid. Discrepancies were found in the specific measurement of the outcome in two studies and in the specific metric. In many other cases, discrepancies were not evaluable due to missing information. No study reported complete outcomes as planned in the published protocol. Communication about the importance of prospective trial registration, including outcome details, should be enforced to reduce the risk of selective outcome reporting bias in oncology acupuncture studies.

Chemotherapy-induced thrombocytopenia (CIT) is a common yet underrecognized complication of systemic chemotherapy, particularly in gastrointestinal (GI) cancers. Despite progress in targeted and immune-based therapies, platinum-based and fluoropyrimidine regimens, especially oxaliplatin-containing protocols, remain standard in GI cancer treatment and are linked to high rates of CIT. This complication often leads to treatment delays, dose reductions, and elevated bleeding risk. This review provides a comprehensive overview of the pathophysiology, clinical implications, and management strategies of CIT in GI malignancies. CIT arises from several mechanisms: direct cytotoxicity to megakaryocyte progenitors, disruption of the marrow microenvironment, thrombopoietin dysregulation, and immune-mediated platelet destruction. Platinum agents, antimetabolites, and immune checkpoint inhibitors can contribute to these effects. Oxaliplatin-induced CIT may occur acutely via immune mechanisms or chronically through marrow suppression. CIT affects 20-25% of solid tumor patients, with highest rates in those receiving gemcitabine (64%), carboplatin (58%), and oxaliplatin (50%). Within GI cancer regimens, FOLFOXIRI and S-1 plus oxaliplatin show higher CIT incidence compared to FOLFIRI and CAPIRI. Thrombocytopenia is graded by severity, from mild (Grade 1-2) to severe (Grade 3-4), and often necessitates treatment adjustments, transfusions, or supportive therapies. Current strategies include chemotherapy dose modification, platelet transfusion, and thrombopoietin receptor agonists (TPO-RAs) like romiplostim and eltrombopag. While platelet transfusions help in acute settings, TPO-RAs may preserve dose intensity and reduce bleeding. Emerging agents targeting megakaryopoiesis and marrow protection offer promising avenues for long-term management.

Background: Biological aging influences cancer outcomes, but its changes during chemotherapy and impact on chemotoxicity in colorectal cancer (CRC) remain underinvestigated. We examined (1) trajectories of biological aging (using Levine Phenotypic Age) during six months of chemotherapy, (2) sociodemographic and clinical risk factors for biological aging, and (3) links between biological aging and chemotoxicity. Methods: Using data from electronic health records (2013-2019) from 1129 adult CRC patients, we computed biological aging (raw Levine Phenotypic Age and its age acceleration [Levine Phenotypic Age-chronological age]) from routine blood tests (e.g., complete blood counts, hepatorenal/inflammatory markers). Chemotoxicity was identified primarily via International Classification of Diseases (ICD-9 and -10) codes. Results: Chemotherapy accelerated biological aging over time. Biological aging at baseline and changes over time predicted chemotoxicity. However, changes in biological aging over time showed stronger associations than baseline biological aging. Advanced cancer stages, higher comorbidity burden, and socioeconomic disadvantage (especially area-level deprivation) were associated with accelerated biological aging at baseline and over time. Biological aging occurred across both young and older adults. Conclusions: Levine Phenotypic Age, computed from routine blood tests in EHRs, offers a feasible clinical tool for aging-related chemotoxicity risk stratification. Validation in diverse cohorts and the development of predictive models are needed.

Advances in molecular diagnostics have enabled precision medicine approaches in pediatric neuro-oncology, with small-molecule drugs emerging as promising therapeutic candidates targeting specific genetic and epigenetic alterations in central nervous system (CNS) tumors. This review provides a focused overview of several small-molecule agents under investigation or in early clinical use, including ONC201, tazemetostat, vorasidenib, CDK inhibitors, selinexor, and aurora kinase A inhibitors, among others. Highlighted are their mechanisms of action, pharmacokinetic properties, early efficacy data, and tolerability in pediatric populations. Despite encouraging preclinical and early-phase results, most agents face limitations due to study heterogeneity, lack of large-scale pediatric randomized trials, and challenges in drug delivery to the CNS. The review underscores the critical need for robust prospective clinical trials for the integration of these therapies into pediatric neuro-oncology care.

In the pursuit of novel anticancer therapies, assessing their selectivity and safety profile towards healthy cells is crucial. This study investigated chlorochalcones, derivatives of 2'-hydroxychalcone containing a chlorine atom, for their impact on human breast cancer cells (MCF-7 and MDA-MB-231), healthy blood cells (erythrocytes, peripheral blood mononuclear cells (PBMCs), platelets), and microvascular endothelial cells (HMEC-1). Our findings demonstrated that chlorochalcones did not detrimentally affect erythrocytes, showing no hemolysis or preserving osmotic resistance and transmembrane potential. They also exhibited minimal impact on normal PBMC viability and varying effects on platelet metabolic activity at therapeutic concentrations. Importantly, these derivatives displayed lower toxicity towards HMEC-1 endothelial cells than towards breast cancer cells, indicating a degree of selectivity. Chlorochalcones have high antiproliferative activity against cancer cells, primarily by inducing apoptosis with virtually no significant impact on cell cycle progression. Their mechanism of action involves the modulation of reactive oxygen species (ROS) levels and induction of mitochondrial dysfunction, including membrane depolarization and reduced mitochondrial mass. Biological activity, including toxicity and ROS modulation, is dependent on the position and number of chlorine atoms. In conclusion, this study highlights the ability of chlorochalcones to effectively target malignant cells while sparing normal circulatory and endothelial cells, thus positioning them as a promising class of candidates for further anticancer drug development.

Plexiform neurofibromas (hereafter called pNF1) are often diagnosed in early childhood and occur in about 30% of neurofibromatosis type 1 (NF1) patients. pNF1 exhibits aggressive growth along a nerve in the body and has substantial potential for progression to malignant peripheral nerve sheath tumors that are rarely curable. There are two recently FDA-approved drugs, selumetinib and mirdametinib, for pNF1 patients who have symptomatic and inoperable plexiform neurofibromas; however, these treatments achieve only approximately 30% tumor shrinkage. Fibroblasts, the most abundant cell types within the pNF1 tumor microenvironment, are implicated in pNF1 growth and invasion; however, how fibroblasts affect a drug response of pNF1 remains poorly understood. In the present study, we focused on contributions of fibroblasts to the drug resistance in pNF1 via their secretome. We employed our established three-dimensional (3D) culture system incorporating human pNF1 tumor cells (Nf1-/-) and primary fibroblasts (Nf1+/-) grown in our patented microfluidic culture chips for monocultures and parallel cocultures in which 3D pNF1 structures and fibroblasts share their secretome without direct cell-to-cell contact. Three-dimensional pNF1 structures in 3D parallel cocultures with fibroblasts exhibited greater drug resistance than ones in monocultures. We found that pNF1 tumor cells showed increased P-glycoprotein expression when incubated with fibroblast-derived conditioned media or parallel cocultured with fibroblasts, compared to control conditions. Pharmacological inhibition of P-glycoprotein partially restored drug sensitivity. Additionally, fibroblasts showed higher resistance to selumetinib and mirdametinib than pNF1 tumor structures, likely due to elevated P-glycoprotein levels. This study is the first to define precise roles of fibroblasts in pNF1 drug resistance, emphasizing the potential of fibroblast-targeted therapies as a promising approach to improve pNF1 treatment outcomes.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, but immune-related hypersensitivity reactions remain a clinical concern. Cadonilimab, a novel PD-1/CTLA-4 bispecific antibody, has demonstrated encouraging antitumor efficacy across various solid tumors; however, hypersensitivity or infusion-related reactions may occasionally occur.

Skin depigmentation or vitiligo-like depigmentation (VLD) is one of the most prevalent cutaneous adverse events during targeted therapies for cancers or autoimmune diseases. The depigmentation is usually with high mental burden and affect the disease treatment, some of which are even clinical markers for good prognosis. This study aimed to explore the underlying immunopathologic mechanisms of VLD induced by targeted therapy for cancer and autoimmune disease as well as vaccine, such as immune checkpoint inhibitors (e.g., programmed death 1/programmed death-ligand 1 and cytotoxic T-lymphocyte antigen-4 inhibitors), v-raf murine sarcoma viral oncogene homolog inhibitors, tyrosine kinase inhibitors, and other targeted agents. Additionally, it examined the clinical presentations, prognostic implications, and management strategies for VLD across oncologic and nononcologic contexts, including cases associated with vaccines and biologics. The development of VLD often correlates with improved therapeutic outcomes, but it presents unique challenges in balancing antitumor efficacy with patients' quality of life. This review integrated insights from oncology, dermatology, and immunology, and underscored the need for multidisciplinary approaches to enhance the understanding, prevention, and management of these complex cutaneous adverse events.

Cytokine release syndrome (CRS) is a potentially severe systemic inflammatory condition triggered by various immunomodulatory therapies, making understanding its pathogenesis critical for improving patient outcomes.

Cancer of the thyroid is a endocrine cancer. Although most patients achieve favorable outcomes with surgical resection, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppression therapy, a subset progresses to advanced or refractory disease. Immune checkpoint inhibitors (ICIs) blocking the PD-1/PD-L1 pathway reactivate T cells, enabling them to identify and eradicate malignant cells, thus reinstating immune surveillance against tumors. This review examines PD-L1 (Programmed Death-Ligand 1) expression in thyroid cancer, exploring its underlying regulatory mechanisms. It also discusses recent advances in PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy. Furthermore, the review highlights regulatory pathways modulating PD-1/PD-L1 expression, including the mTOR pathway, androgen receptor (AR), and the CKS1B/STAT3 pathway. Notably, it summarizes recent clinical developments, such as combination regimens pairing PD-L1 blockade with mutation-targeted therapies, for which the median OS of the targeted combination therapy group was 14.7 months. This therapy has achieved the longest median OS for anaplastic thyroid carcinoma (ATC) patients so far. Additionally, the review examines innovative treatment modalities, offering a thorough synthesis of the existing state and emerging trends in PD-1/PD-L1 immunotherapies.

Melanoma is an exceptionally aggressive form of skin cancer, and its prognosis becomes dire once it metastasizes. Although substantial progress has been made in the field of immunotherapy, significant hurdles such as tumor cell immune evasion, the tumor microenvironment (TME), and immune-related adverse effects persist. Recent advancements in nanotechnology offer promising solutions to these challenges by enhancing targeting, stability, and delivery of immunotherapeutic agents. Nano-immunotherapy, which synergizes nanotechnology with immunotherapy, is evolving into a groundbreaking approach for melanoma treatment. Various nanoparticles, including liposomes, dendrimers, and polymeric nanoparticles (PNPs), are under investigation to boost immune responses, deliver immune checkpoint inhibitors (ICIs), and modulate the TME. These nanoparticles can be engineered for precise drug delivery, minimizing off-target effects and enhancing therapeutic outcomes. Moreover, the encapsulation of sensitive molecules such as cytokines, vaccines, and antibodies within nanoparticles ensures their stability and bioavailability. This review delves into the recent advancements in nano-immunotherapy for melanoma, emphasizing the mechanisms through which nanoparticles enhance immune activation and counteract the immunosuppressive TME. Additionally, we address the challenges of translating these nanomaterials into clinical settings, including optimizing nanoparticle design, ensuring safety, and achieving robust immune activation. This review provides a detailed examination of the current landscape and future potential of nano-immunotherapy as a promising strategy for melanoma treatment.

Background: Prostate cancer (PCa) poses a significant health burden for men, with docetaxel constituting the primary therapeutic option for patients with metastatic PCa. However, the mechanisms governing docetaxel resistance remain incompletely understood. Several studies have implicated the role of the extracellular matrix (ECM) stiffness in cancer drug resistance, yet the precise role of ECM stiffness in docetaxel resistance in PCa remains elusive. The aim of this study was to explore the influence of ECM stiffness on docetaxel resistance in PCa and elucidate the underlying molecular mechanisms, thereby providing novel insights into PCa treatment. Methods: Polyacrylamide gels of varying stiffness were utilized to mimic different ECM stiffness conditions. The sensitivity of PCa cells to docetaxel was evaluated using CCK-8, TUNEL staining, flow cytometry, and western blotting. RNA-seq was employed to analyze the transcriptomic effects of different ECM stiffness on PC-3 cells. Western blotting, qPCR, and siRNA were utilized to validate the regulatory role of the key gene in the sensitivity of PCa cells to docetaxel under varying stiffness conditions. Results: Our findings indicate that high ECM stiffness enhances docetaxel resistance in PCa cells by inhibiting docetaxel-induced apoptosis. This process is mediated through the integrin-related mechanotransduction pathway. Specifically, high ECM stiffness upregulates the expression of PRRX1, thereby promoting docetaxel resistance in PCa cells. Conclusions: High ECM stiffness promotes docetaxel resistance in PCa, with PRRX1 identified as a pivotal gene in this process. These findings contribute to a deeper understanding of the mechanisms underlying docetaxel resistance in PCa and may inform the development of novel therapeutic strategies.

Neuroblastoma, a prevalent and lethal extracranial solid tumor in childhood, remains a significant challenge in pediatric oncology worldwide. High-risk neuroblastoma (HR-NB) is particularly aggressive and linked to a poor prognosis due to the limited availability of effective treatments. The aberrant amplification of the MYCN gene is a critical genetic alteration observed in neuroblastoma conferring poorer clinical outcomes. To date, no drugs targeting N-Myc have been approved. In this study, we successfully established a novel high-throughput screening system targeting N-Myc and identified the first small molecule inhibitor, N78, which exhibits selective, high affinity for N-Myc over c-Myc. N78 selectively degrades N-Myc, suppresses the expression of its target genes, and effectively diminishes the viability of MYCN-dependent tumor cells. Notably, N78 demonstrates acceptable tolerability and induces significantly enhanced tumor regression in vivo compared to Myci975, a leading candidate among c-Myc/N-Myc inhibitors. Mechanistically, N78 promotes the phosphorylation of N-Myc at threonine-58, leading to its degradation via the ubiquitin-proteasomal pathway. This study presents the first selective N-Myc inhibitor N78, and highlights the promise of small-molecule N-Myc inhibitors as both chemical probes and potential anti-cancer therapies for neuroblastoma.

Tumor vascular normalization has emerged as a promising strategy to potentiate immune checkpoint blockade in solid tumors. Here, we unveil a previously unrecognized NAT10/XIST/YAP1/VEGFA signaling axis driving vascular abnormalization in gastric cancer (GC) and demonstrate its therapeutic potential in remodeling the tumor immune microenvironment. Through integrative analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and functional validation, we identified NAT10-mediated N4-acetylcytidine (ac4C) modification as a critical stabilizer of lncRNA XIST. Mechanistically, XIST recruits hnRNPK to facilitate YAP1 nuclear translocation, thereby activating TEAD4-dependent VEGFA transcription and promoting angiogenic programming. Genetic or pharmacological inhibition of NAT10 with Remodelin attenuated VEGFA secretion, enhanced pericyte coverage and basement membrane integrity, and normalized tumor vasculature in syngeneic GC models. Moreover, we found that NAT10 inhibition reshaped the immune landscape by upregulating CXCL9/10/11 chemokines, promoting cytotoxic lymphocyte infiltration while reducing Treg populations. Strikingly, combining Remodelin with the YAP1 inhibitor Verteporfin synergistically augmented anti-PD-1 efficacy, significantly suppressing tumor growth in immunocompetent mouse models. Our findings not only elucidate an ac4C-dependent epitranscriptomic mechanism governing vascular-immune crosstalk but also propose a novel combinatorial therapeutic strategy to overcome resistance to immune checkpoint blockade in GC.

Platinum-based chemotherapy is the standard treatment for advanced non-small cell lung cancer (NSCLC); however, innate and acquired resistance is a major obstacle. To determine the transcriptional regulators of resistance, we first classified three-dimensional tumor spheroids derived from 11 NSCLC cell lines into cisplatin-sensitive or -resistant groups based on their cisplatin sensitivity and selected signature genes that were differentially altered between the groups. Using reverse engineering methods and functional validation, cAMP response element-binding protein 1 (CREB) was identified as a major regulator of cisplatin resistance. Among the putative target genes of CREB responsible for cisplatin resistance, cisplatin treatment significantly decreased the occupancy of CREB in the regulatory regions of TNKS and KDM6A in cisplatin-sensitive cells, but not in resistant cells, resulting in decreased expression of these protein in the sensitive group. Furthermore, CREB knockdown led to increased sensitivity to cisplatin with reduced levels of TNKS and KDM6A in both cisplatin-resistant tumor spheroids and tumors in a xenograft mouse model. In conclusion, our study delineates the role of CREB in cisplatin resistance and suggests that CREB inhibition is a potential therapeutic strategy for cisplatin-resistant NSCLCs.

Rationale: The tumor microenvironment (TME) plays a pivotal role in cancer progression, with tumor-associated macrophages (TAMs) serving as key contributors. Immunosuppressive M2-type TAMs are associated with poor prognosis and treatment resistance, highlighting the need for strategies to reprogram these cells into pro-inflammatory M1 phenotypes. To address this, we developed a TME-reshaping nanoplatform combining the tumor-targeting capability of M1 macrophage-derived nanovesicles (M1NVs) with the immunomodulatory and catalytic properties of hollow, virus-spiky hMnOx nanozymes. This approach aims to enhance chemotherapy delivery while simultaneously reversing immunosuppression and boosting antitumor immunity. Methods: We engineered a biomimetic nanoplatform by physically co-extruding M1NVs with hMnOx nanozymes. The platform was evaluated in a malignant melanoma model characterized by M2 TAM infiltration, using the first-line chemotherapeutic agent dacarbazine (DTIC) as a model drug. The system's tumor-targeting ability, cytotoxicity, and immunomodulatory effects were assessed. Additionally, the capacity of hMnOx nanozymes to induce immunogenic cell death (ICD) and promote antigen presentation was investigated. Results: The nanoplatform demonstrated precise tumor-targeted delivery of DTIC via M1NVs, effectively inducing tumor cell death. The combination of M1NVs and hMnOx nanozymes successfully repolarized M2 TAMs into pro-inflammatory M1 macrophages, alleviating immunosuppression and enhancing immunotherapy efficacy. Furthermore, hMnOx nanozymes triggered ICD and improved antigen presentation, amplifying antitumor immune responses. The fabrication process was simple and scalable, underscoring the platform's potential for clinical translation. Conclusion: This study presents a novel nanozyme-boosted biomimetic macrophage-derived nanovesicle system that integrates precise tumor targeting, chemotherapy delivery, and TME immunomodulation. By repolarizing TAMs and enhancing antitumor immunity, the platform offers a promising strategy to overcome treatment resistance in immunosuppressive tumors. Its scalable production and high clinical potential make it a viable candidate for future cancer therapy applications.