Background: The melanoma-associated antigen-A1 (MAGE-A1) demonstrates tumor-restricted expression patterns in diverse malignancies, positioning it as an attractive therapeutic target. This investigation aimed to engineer and validate a novel antibody-drug conjugate with oxaliplatin targeting MAGE-Al (MIg-OXA), a novel antibody-drug conjugate targeting MAGE-A1, while assessing its therapeutic potential against MAGE-A1-expressing lung adenocarcinoma through both cellular and animal models. Methods: We generated a MAGE-A1-specific immunoglobulin G (IgG) antibody (MIgG) and subsequently conjugated it with oxaliplatin (OXA) to produce MIgG-OXA. The conjugate's binding specificity and cellular uptake were verified through cell-based enzyme-linked immunosorbent assay (ELISA), flow cytometric analysis, and immunofluorescence microscopy. Functional assessments included Cell Counting Kit-8 (CCK-8) viability assays, transwell migration studies, apoptosis detection, and antibody-dependent cell-mediated cytotoxicity (ADCC) evaluation to determine anti-neoplastic activity in cultured cells. Therapeutic efficacy in living organisms was examined using lung adenocarcinoma (LUAD) xenograft-bearing athymic mice. Results: Our data confirmed successful synthesis and validation of MIgG-OXA, which demonstrated selective recognition of MAGE-A1-expressing LUAD cell populations and facilitated controlled OXA release. When compared to unconjugated OXA, MIgG-OXA displayed enhanced tumor suppression in both cultured LUAD cells and transplanted tumor models. Conclusion: These findings collectively indicate that MIgG-OXA holds substantial promise as a precision therapeutic approach for patients harboring MAGE-A1-positive LUAD.

The E26 transformation-specific family of transcription factors regulates the cell cycle and apoptosis that are crucial for carcinogenesis. More specifically, the PEA3 subfamily-comprising ETS variant (ETV) transcription factors ETV1, ETV4, and ETV5-has been implicated in multiple oncogenic signaling pathways and chemotherapy resistance. While cisplatin is still a widely used chemotherapeutic treatment for ovarian cancer, its therapeutic efficacy is sometimes limited by the induction of resistance mechanisms. The present study investigates the potential role of PEA3 subfamily genes in cisplatin resistance in ovarian cancer through comprehensive in silico analyses.

This study aimed to establish and validate a population pharmacokinetic model for rituximab during induction therapy in treatment-naive patients with diffuse large B-cell lymphoma, identify covariates affecting key pharmacokinetic parameters, and predict exposure. This retrospective study included newly diagnosed patients receiving rituximab-containing induction regimens. Blood samples were collected before the next dose and after completion of the current dose across different chemotherapy cycles during the induction therapy; plasma concentrations were measured by chemiluminescent immunoassay. A nonlinear mixed-effects model was developed and externally validated. Individual parameters were obtained using empirical Bayesian methods, and first-cycle trough concentrations were predicted. For model building, 45 patients and 115 samples were included; external validation used 12 patients and 28 samples. Rituximab pharmacokinetics were described by a two-compartment model. Representative estimates were: clearance 0.0181 L/h, central volume 8.12 L, intercompartmental clearance 0.0213 L/h, peripheral volume 29.2 L. Albumin-globulin ratio was the final covariate and significantly affected clearance. Validation indicated good stability and predictive performance. Predicted first-cycle trough concentrations were below the reference efficacy threshold, and lower troughs were associated with smaller albumin-globulin ratios. This model quantified the effect of albumin-globulin ratio on clearance and suggests a risk of insufficient rituximab exposure during induction therapy, supporting future individualized dosing and therapeutic drug monitoring.

Anisodus tanguticus (Maxim.) Pascher has been documented in Tibetan ethnomedicine. Traditional records indicate that A. tanguticus has traditionally been used to relieve pain, treat parasitic infections, and heal skin wounds caused by viral infections. A. tanguticus is rich in tropane alkaloids, including anisodamine, scopolamine, and atropine, which are pharmacologically active constituents with well-known parasympatholytic effects. These alkaloids have shown promise in controlling cancer cell proliferation and metastasis, with preclinical studies indicating antitumor activity against liver, breast, and colorectal cancers. The extraction of A. tanguticus traditionally involves methods such as juice pressing or boiling; however, modern techniques like ultrasonic, reflux, and supercritical fluid extraction have enhanced alkaloid yield and quality. While the pharmacological properties of A. tanguticus suggest that some constituents of A. tanguticus may have preclinical antitumor relevance, most studies remain preclinical, and clinical data is limited. This review highlights the need for further pharmacological, toxicological, and translational studies. Current evidence suggests that A. tanguticus and several of its constituents exhibit preclinical antitumor activity; however, their clinical relevance remains uncertain, and further pharmacological, toxicological, and clinical validation is required. This narrative review summarizes the traditional use, phytochemical composition, extraction methods, antitumor-related findings, and proposed mechanisms of A. tanguticus, while highlighting the need for further pharmacological, toxicological, and translational studies.

This study aimed to develop a dynamic-static combined Neiyanggong intervention for breast cancer patients undergoing chemotherapy and to evaluate its effectiveness in alleviating cancer-related fatigue, with sleep quality assessed as a secondary outcome.

Deficient DNA mismatch repair/microsatellite instability-high (dMMR/MSI-H) cancers are very sensitive to immune checkpoint inhibitors (ICIs), yet their use is frequently complicated by immune-related adverse events (irAEs). Our study analyzed the impact of grade ≥3 irAEs (immune-related severe adverse events (irSAEs)) on survival in patients with dMMR/MSI-H digestive cancers treated with ICIs.

The pyripyropenes A-X represent a family of 24 alkaloids isolated from fungi, mainly Aspergillus and Penicillium species, over the past 30 years. Numerous analogues have been isolated from fungi or (hemi)synthesized to investigate structure-activity relationships. The leader product in the series remains the first identified natural product pyripyropene A (Pyri-A), known as a highly potent and selective inhibitor of acyl CoA:cholesterol acyltransferase 2 (ACAT2). The present review retraces the products history, from their discovery to the characterization of the target engagement, the cellular mechanism of action and bioactivities. In parallel to the identification of naturally occurring pyripyropenes and the synthesis of derivatives, studies have progressed in three directions. First, the development of agricultural insecticides from Pyri-A led to discovery and worldwide commercialization of afidopyropen (Inscalis®) to protect crops against sucking insects. Second, the highly potent and selective targeting of ACAT2, largely expressed in human liver cells notably, drove the design of analogues aimed at regulating cholesterol metabolism for the treatment of metabolic and cardiovascular diseases. Third, the emerging roles of ACAT2 as a regulator of tumor cell proliferation and anticancer immune response call for the development of the pyripyropenes in oncology. A few tumor-active pyripyropene derivatives targeting ACAT2 have been identified recently. The review underlines the evolution of research in this domain, from the fungal production to the insecticidal action, and from the treatment of atherosclerosis to cancers. The pyripyropene saga is alive and well.

Lymphoma is a heterogeneous group of malignant neoplasms originating from the lymphohematopoietic system, with relapse, drug resistance, and treatment-related toxicity remaining major clinical challenges. Owing to their structural diversity, capacity to modulate multiple signaling nodes, and potential to reshape the tumor immune microenvironment, natural products have emerged as a promising source for anti-lymphoma drug development and for sensitizing combination regimens. This review summarizes the pharmacological activities, mechanisms of action, preclinical evidence, and translational limitations of flavonoids, quinones, polyphenols, alkaloids, terpenoids, saponins, and polysaccharides. Key signaling cascades and the tumor immune microenvironment are additionally incorporated. However, translational potential is substantially limited by insufficient in vivo exposure, a disconnect between pharmacokinetics and pharmacodynamics (PK/PD), limited selectivity of pro-oxidant effects, a narrow therapeutic window, structural heterogeneity, and a lack of standardized formulations. Collectively, current evidence suggests that natural products should be repositioned from empirically derived cytotoxic candidates to mechanism-guided adjunctive agents for combination therapy in lymphoma. Future studies should further integrate PK/PD relationships, lymphoma molecular subtypes, tumor immune microenvironment status, and standardized formulation evaluation to better define their indications and translational boundaries.

Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with a poor prognosis in refractory and recurrent patients. RRx-001 is a promising anticancer agent currently under investigation in hematological malignancies; however, its therapeutic effects on BL are not clear. In this study, RRx-001 was found to inhibit the proliferation of BL cells and induce a DNA damage response. RRx-001 can induce apoptosis through caspase cascades with increasing cleavage of Caspases 8, 9, and 3. RRx-001 can also upregulate the expression of DR4, DR5, Bax, and cytochrome C and decrease the expression of Bcl-2, Mcl-1, and XIAP. RRx-001 promotes the accumulation of reactive oxygen species and triggers endoplasmic reticulum (ER) stress in BL cells, both these alterations contribute to RRx-001-induced apoptosis. Additionally, RRx-001 regulates MAPK pathways, and JNK/p38 MAPK signaling functions as a critical hub linking ER stress and oxidative DNA damage. Importantly, RRx-001 also functions as a regulator of CD47 and c-Myc, strongly inhibiting them both in vitro and in a BL cell tumor-bearing mouse model. The overexpression of CD47 increases the proliferation and partially inhibits the apoptosis of BL cells induced by RRx-001. Hence, the findings of this study provided new evidence that RRx-001 may serve as a therapeutic drug for treating BL.

Resistance to 5-fluorouracil (5-FU) and oxaliplatin (OXT) remains a major cause of treatment failure in colorectal cancer (CRC). Luteolin, a dietary flavonoid with anticancer properties, has shown therapeutic potential in various malignancies, but its effects on chemotherapy-resistant CRC remain poorly understood. In this study, we investigated whether luteolin restores chemosensitivity in 5-FU-resistant (SNUC5/5-FUR) and OXT-resistant (SNUC5/OXTR) CRC cells and explored the underlying molecular mechanisms. Luteolin reduced cell viability and induced apoptosis in both resistant cell lines. Mechanistically, luteolin suppressed β-catenin expression by downregulating ten-eleven translocation (TET) proteins, increasing DNA methyltransferase (DNMT) expression, enhancing CpG methylation, and reducing TET1 occupancy at the β-catenin promoter. Luteolin also decreased thymine DNA glycosylase (TDG) expression, disrupted the TET1/TDG interaction, and reduced TDG recruitment to the β-catenin promoter. Consistently, knockdown of either TET1 or TDG decreased β-catenin expression, while luteolin further enhanced apoptosis in siTET1-or siTDG-transfected resistant cells. Additionally, luteolin attenuated intracellular reactive oxygen species accumulation and potentiated the cytotoxic effects of 5-FU and OXT in resistant CRC cells. These findings demonstrate that luteolin reverses chemoresistance by suppressing the TET1/TDG-β-catenin axis through epigenetic regulation and modulation of intracellular redox homeostasis, supporting its potential as an adjuvant for CRC chemotherapy.

Hematological malignancies are highly heterogeneous diseases characterized by dysregulated signaling pathways and limited durable therapeutic responses. Calcium homeostasis has emerged as a critical regulator of cancer cell fate, yet the role of the sodium/calcium exchanger 1 (NCX1/SLC8A1) in leukemogenesis remains poorly defined. In this study, we comprehensively investigated the biological significance and therapeutic potential of NCX1 across major hematological malignancies by integrating transcriptomic analyses, protein-protein interaction networks, experimental validation, and in silico drug repurposing strategies. NCX1 was highly expressed in HL-60, K-562, and Jurkat cells compared to HaCaT controls. Network analyses revealed that NCX1 interacts with key regulators of calcium signaling, immune response, and signal transduction. In AML and CML patient datasets, a strong positive correlation was observed between NCX1 expression and immune-related pathways, while a negative correlation was observed with translation-related processes. Molecular docking analyses demonstrated that several clinically approved compounds, particularly imatinib and nilotinib, interact with NCX1. Molecular dynamics simulation was performed to evaluate the binding stability and safety of imatinib. Remarkably, the comprehensive analysis showed that imatinib exhibited a stable molecular dynamics profile. All these findings have demonstrated NCX1 as a biologically informative marker of myeloid differentiation and a promising therapeutic weak point within calcium signaling networks in hematological malignancies, providing a rationale for future functional and single-cell validation studies.

DNA integrity is essential for cellular function and chemotherapy response, but real-time, single-cell monitoring of DNA damage has been difficult to achieve. In this study, we constructed an electrochemical biosensor using a DNA-modified platinum nanoelectrode (PtNE/DNA) combined with fast-scan voltammetry (FSV) at 30 kV s-1 for dynamic detection of DNA damage in a single living cell. The sensing platform utilizes a ferrocene-labeled hairpin DNA probe that specifically recognizes structural damage, while the high temporal resolution and strong anti-interference capability are provided by the FSV technology. We successfully monitored real-time DNA damage in a single HeLa cell treated with chemotherapeutic agents including doxorubicin (DOX), cisplatin (CDDP), and paclitaxel (PTX). Distinct kinetic profiles were observed: DOX elicited the most rapid and severe damage, CDDP induced intermediate progression, and PTX resulted in delayed and attenuated effects. Furthermore, we revealed enantioselective cytotoxicity of chiral carbon dots (D-CDs and L-CDs), with L-CDs showing significantly higher toxicity. These results demonstrate the utility of our approach in assessing drug sensitivity and nanomaterial biocompatibility at the single-cell level, providing a valuable tool for advancing precision medicine and toxicological research.

Given the limitations of the existing monoclonal antibody (mAb)-based therapies, more efficient and safer small-molecule-based checkpoint therapies targeting the programmed cell death-1 (PD-1) / programmed cell death ligand-1 (PD-L1) axis are gaining growing attention and urgently required.

All-trans retinoic acid (ATRA) is an essential agent in the treatment of acute promyelocytic leukemia (APL). However, careful monitoring is required due to its potential side effects, particularly intracranial hypertension (IH).

The introduction of immune checkpoint inhibitors targeting the programmed death-1 (PD-1) axis represented a major therapeutic advance, enabling long-term survival, and even cure, in a subset of patients, an outcome previously considered unattainable in metastatic disease. However, most patients do not yet derive sustained benefit. Despite extensive efforts to define biomarkers, identify mechanisms of sensitivity and resistance, and translate these insights into therapeutic strategies, attempts to intensify PD-1-based therapy have failed to improve long-term survival. Extending durable benefit and achieving cure in a broader population will require a deeper understanding of mechanisms of resistance, the development of novel immunotherapeutics, and more precise personalization of treatment strategies.

KRAS driver mutations have classically been considered undruggable by direct inhibitors in non-small cell lung cancer (NSCLC) as well as other solid tumors. However, recent advances have led to the first successful direct KRAS inhibitors, beginning with the development of KRASG12C inhibitors targeting the inactive GDP-bound state of KRAS. These initial KRASG12C (OFF) inhibitors demonstrated real but modest activity in KRASG12C-mutated mNSCLC. The development of more potent optimized KRASG12C (OFF) inhibitors has sought to improve upon the clinical activity of the initial raft of KRASG12C (OFF) inhibitors. Combination therapy with PD-1 inhibitors, as well as other classes of drugs, is also under intense investigation in NSCLC and other solid tumors. Nevertheless, primary and acquired resistance, as well as a variable and peculiar tendency to autoimmune hepatitis, have complicated efforts to develop this class of inhibitors in KRASG12C-mutated mNSCLC. In parallel, new direct inhibitor classes have emerged recently, including tri-complex ON-state inhibitors and dual-state ON/OFF inhibitors capable of targeting not only KRASG12C but also other KRAS mutations, as well as panKRAS and panRAS strategies. These agents have the potential to broaden the activity of initial KRASG12C (OFF) inhibitors and to avoid certain mechanisms of resistance and toxicity, but remain early in development with limited data. The KRAS therapeutic landscape is evolving rapidly, with many promising competing strategies each seeking to distinguish itself in an increasingly crowded therapeutic landscape.

Immune checkpoint inhibitors (ICIs), including the programmed cell death protein-1 (PD-1) inhibitor pembrolizumab, have revolutionized metastatic urothelial carcinoma management but are frequently associated with cutaneous immune-related adverse events, including drug-induced bullous pemphigoid (DIBP). We present the case of an 81-year-old man with PD-L1-negative metastatic high-grade papillary urothelial carcinoma with a generalized, pruritic, bullous eruption following treatment with pembrolizumab. Histopathology and direct immunofluorescence confirmed bullous pemphigoid (BP). This case underscores the diagnostic challenges of DIBP. Clinicians must maintain a high index of suspicion and consider early transition to steroid-sparing agents such as rituximab in refractory cases. Timely dermatologic referral and close multidisciplinary coordination are essential.

The aim of this study was to evaluate outcomes of treatment with cemiplimab in patients with metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC) not amenable to surgery or radiotherapy in a single tertiary center. Demographic, histologic, and clinical data were retrospectively collected for patients treated with cemiplimab between November 2018 and March 2023. The primary objective was overall response rate (ORR), with secondary objectives including progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Among 31 patients, 20 (64.5%) achieved a complete response, 6 (19.4%) achieved a partial response, and 2 (6.5%) experienced disease progression. Our findings yielded an ORR of 83.9%, which exceeded the 46.1% reported in the EMPOWER-CSCC 1 trial. The 2-year OS was 73.5%, comparable to the 73.3% reported in EMPOWER-CSCC 1. Adverse events occurred in 24 patients (77.4%). These findings provide additional real-world evidence supporting the efficacy of cemiplimab in advanced cSCC, with a substantial proportion of patients achieving complete response, including after limited treatment exposure; further studies are needed to better define optimal treatment duration and dosing strategies.

Anti-angiogenic therapy benefits vary, with response rates of 40 to 70%, highlighting the need for early biomarkers to identify responders. We developed an automated machine learning framework that uses delta quantitative vascular morphometry features from standard contrast-enhanced CT to evaluate treatment response. This workflow combines automated tumor and vessel segmentation with feature extraction from routine scans for clinical use. Shapley additive explanations (SHAP)-based attributions identify key vascular and clinical features, providing meaningful, imaging-visible evidence aligned with therapy targets beyond traditional radiomics. Using baseline and follow-up CTs from 163 patients with lung cancer, we built three models using fivefold cross-validation, with the delta-merge model achieving high accuracy (area under the receiver operating characteristic curve = 0.842 internally, 0.806 externally). SHAP analysis uncovered an "arterial-dominant, venous-adaptive" pattern, where arterial involvement and venous recovery distinguish responders. This automated workflow and visualization support early, imaging-based response assessment and personalized treatment.

Ninety percent of drugs fail during clinical trials, mainly due to lack of clinical efficacy. Recent developments in in vitro models such as 3D tumor heterospheroids have led to improvements in failure rates, but the relative lack of standardized evaluation methods for 3D cultures limits their utility in high-throughput screening. Optical coherence tomography (OCT) shows significant promise for high-throughput screening of 3D models; however, the optimal classification model and key image features for assessing drug efficacy in OCT images of spheroids has yet to be explored in detail. In this study, we investigate whether OCT combined with machine learning methods can be used to identify biomarkers of drug efficacy in 3D tumor spheroid models. We further compare the performance of two different models to determine the optimal configuration for accurate classification. Volumetric OCT images were acquired of co-cultured HT29 spheroids treated with 3 different concentrations of cisplatin. A two-dimensional multi-view ResNet model and a three-dimensional ResNet model were used to classify the images and to identify key image features associated with each group. Differences between spheroids treated with different concentrations of cisplatin are clearly visible in the OCT images. Our model was able to classify the images based on cisplatin concentration with 71.9% accuracy using the 2D multi-view model and 91.2% accuracy using the 3D model. Key features in the 3D model significantly improved the model accuracy. These results underscore the possibility that OCT could be used for high-throughput screening of drugs using 3D in vitro models and highlight key identifying features for further investigation.