Gastric cancer (GC) is one of the most common types of cancer worldwide, with limited therapeutic options available for patients with advanced‑stage disease. Claudin 18.2 (CLDN18.2) has emerged as a popular target for the diagnosis and treatment of GC. Although antibody‑drug conjugates (ADCs) and radionuclide‑drug conjugates (RDCs) targeting CLDN18.2 have been assessed, to the best of our knowledge, no comparative studies have evaluated the efficacy and toxicity profiles of these two treatment modalities. The present study aimed to compare the antitumor efficacy and toxicity of ADCs and RDCs derived from the same anti‑CLDN18.2 monoclonal antibody (mAb) targeting CLDN18.2‑positive tumors. Modified DFO/DOTA‑SYSA1801mAb, labeled with ⁸⁹Zr and ¹⁷⁷Lu, was used in cell‑based assays, positron emission tomography and biodistribution studies to evaluate its targeting specificity. In an NUGC‑4‑CLDN18.2 xenograft tumor model, the antitumor efficacy and toxicity of the mAb (SYSA1801mAb), as well as the ADC (SYSA1801) and RDC ([¹⁷⁷Lu]Lu‑DOTA‑SYSA1801mAb), and their combinations in different sequences (ADC→RDC and RDC→ADC), were systematically assessed. [⁸⁹Zr]Zr‑DFO‑SYSA1801mAb demonstrated notable in vitro stability and effectively imaged tumors with high CLDN18.2 expression. [¹⁷⁷Lu]Lu‑DOTA‑SYSA1801mAb exhibited strong tumor‑targeting ability, with significantly higher tumor uptake than other tissues. By day 145, the complete remission (CR) rate in the ADC group was 60%, with an overall survival (OS) rate of 60%. In the ADC→RDC group, the CR and OS rates were both 40%. The OS rates in the RDC, RDC→ADC, mAb and control groups were all 0%. The ADC group exhibited minimal changes in hematological parameters and hepatic/renal function, whereas the RDC and RDC→ADC groups showed more significant changes. These preclinical findings suggested that ADC monotherapy may demonstrate superior efficacy and safety profiles when compared with RDC monotherapy. Furthermore, sequential combination therapy that starts with ADC appears to be more favorable than approaches that start with RDC. Although ADC→RDC sequential therapy did not significantly outperform ADC monotherapy in this model, it may serve as an effective subsequent treatment strategy.

Despite the established clinical efficacy of oxaliplatin in colorectal cancer (CRC), resistance to this platinum‑based agent continues to pose a significant therapeutic challenge. Increased exportin 1 (XPO1) expression in CRC has been linked to chemoresistance, while KPT‑330, a selective XPO1 inhibitor, has exhibited potential in enhancing platinum drug effectiveness in other cancer types. The present study explored the synergistic effects of KPT‑330 and oxaliplatin in oxaliplatin‑resistant CRC models. Oxaliplatin‑resistant cell lines (HCT116/L‑OHP and HCT8/L‑OHP) were developed, exhibiting elevated XPO1 expression as demonstrated by western blotting. A range of in vitro assays (Cell Counting Kit‑8 assays, ethynyldeoxyuridine assays, crystal violet staining, transmission electron microscopy and flow cytometry) and an in vivo subcutaneous xenograft model in nude mice were used to evaluate the combination therapy. Co‑treatment with KPT‑330 and oxaliplatin induced G2/M phase arrest and mitochondrial dysfunction, thereby triggering apoptosis and ferroptosis. Mechanistically, the combination therapy of KPT‑330 and oxaliplatin promoted the nuclear retention of p53, which in turn upregulated p21 and downregulated solute carrier family 7 member 11. In vivo, the combination therapy significantly enhanced tumor sensitivity to oxaliplatin. These results suggested that KPT‑330 restored oxaliplatin sensitivity in resistant CRC by facilitating p53 nuclear retention, presenting a promising approach to overcome chemoresistance through dual modulation of cell cycle arrest and ferroptosis pathways.

Leucine‑rich repeat‑containing protein 59 (LRRC59), a 244‑amino‑acid endoplasmic reticulum membrane protein, is implicated in the tumorigenesis of multiple malignancies. However, its functional significance in colorectal cancer (CRC) remains poorly understood. In the present study, LRRC59 expression in CRC tissues was evaluated using immunohistochemistry and western blotting. Colony formation, Cell Counting Kit‑8, wound healing and Transwell assays, in in vivo xenograft models, were used to evaluate the effect of LRRC59 on CRC progression. Apoptosis was analyzed using flow cytometry and western blotting. The interaction between LRRC59 and the protein kinase RNA‑like endoplasmic reticulum kinase (PERK) pathway was verified using the starBase database and western blotting. It was found that LRRC59 expression was significantly higher in CRC tissues than in normal tissues. LRRC59 knockdown in HCT116 and LoVo cells inhibited proliferation, migration and invasion and promoted apoptosis, and the PERK pathway was significantly activated. In vivo subcutaneous tumorigenesis assays corroborated these in vitro findings. Treatment with a PERK pathway‑specific inhibitor reduced the apoptosis of HCT116 and LoVo cells with LRRC59 knockdown. These findings suggest that LRRC59 is not only significantly upregulated in CRC but also mechanistically drives tumor progression by coordinating pro‑oncogenic processes, including enhanced proliferation, migration and invasion. Importantly, mechanistic evidence was provided that LRRC59 inhibits apoptosis by suppressing the PERK signaling axis, identifying this molecule a target in the development of CRC therapeutic strategies.

Alternative splicing is a crucial mechanism of gene regulation that can be dysregulated in cancer. In pituitary neuroendocrine tumors (PitNETs), alteration in the serine/arginine-rich splicing factors (SRSFs) has been reported. SRSFs phosphorylation and activation is mediated by serine-arginine protein kinase 1 (SRPK1). SRPK1 is considered a proto-oncogene and its inhibition by small molecule inhibitors SRPIN340 and SPHINX31 have shown antitumoral effects via the SRPK1-SRSF1-VEGF pathway modulation in different cancer types. No previous studies have evaluated SRPK1 inhibitors in pituitary tumors. The present work explores the antitumoral effects of SRPIN340 and SPHINX31 in rat and human GH-secreting pituitary tumoral cells. First, immunoblot results showed a reduction of SRSFs phosphorylation induced by both compounds, demonstrating the efficacy of these molecules in inhibiting SRPK1 activity. SRPIN340 reduced GH4C1 cell proliferation (-31.7 (33.6)%, p <0.05 vs control cells at 1µM), cell viability (-16.4 (27.9)%, p<0.05 vs control cells at 1µM), cell migration (-65.0 (46.3)%, p<0.001 vs control cells at 10µM) and induced cell apoptosis (+40.5 (26.6)%, p<0.05 vs control cells at 10µM). Moreover, SRPIN340 significantly decreased both transcript (-56.3 (38.6)%, p<0.01 vs control cells) and protein levels (-33.5 (3.4)%, p<0.05 vs control cells) of the pro-survival VEGF164a isoform. Similar results have been obtained with SPHINX31. Interestingly, cells incubation with the recombinant VEGF164a protein impaired the decrease of cell migration and cell viability mediated by both SRPK1 inhibitors. As for GH-secreting primary cultures from GH-PitNETs, SRPIN340 incubation resulted in reduced VEGF165a expression (-50.6% vs control cells) and GH secretion (-14.45 (8.17)%, p < 0.05 vs control cells). In conclusion, SRPK1 inhibition may represent a novel approach to exert antitumoral effects in somatotroph tumoral cells via SRPK1-SRSF1-VEGF pathway regulation.

Female adnexal tumor of Wolffian origin (FATWO) is an exceedingly rare gynecologic neoplasm characterized by nonspecific clinical manifestations and diagnostic challenges. This article presents a case of an incidentally discovered FATWO in a postmenopausal woman, with a literature review.

A 54-year-old postmenopausal woman was found to have a 5.2-cm solid mass in the left adnexa during routine examination. Ultrasonography revealed a well-circumscribed lesion with detectable blood flow, while computed tomography (CT) scan suggested an ovarian origin. Tumor markers were within normal limits, and the patient remained asymptomatic. Single-port laparoscopic exploration identified a 5-cm solid ovarian nodule with an intact capsule. Intraoperative frozen section analysis suggested FATWO, prompting subsequent total hysterectomy with bilateral salpingo-oophorectomy. No adjuvant therapy was administered postoperatively, and the patient showed no evidence of disease progression during 1-year follow-up.

FATWO exhibits a potentially malignant biological behavior. For postmenopausal patients, total hysterectomy with bilateral salpingo-oophorectomy is recommended. Postoperative management should be individualized. Current evidence regarding treatment strategies for reproductive-age patients remains limited, warranting further investigation to optimize clinical decision-making.

The Toll-like receptor (TLR) 7/8 agonist resiquimod has shown promise for precancerous lesions of cutaneous squamous cell carcinoma (cSCC) but remains unexplored as a treatment for cSCC. Additionally, ablative fractional laser (AFL) has been shown to enhance the efficacy of TLR7 agonist in mouse tumor models. This study investigates the efficacy of intratumoral resiquimod formulated into a sustained-release gel (RSQ-gel) in a cSCC mouse model and compares RSQ-gel with topical imiquimod (IMQ) cream, a clinically approved TLR7 agonist. We further examine whether adjuvant AFL enhances the efficacy of RSQ-gel.

A syngeneic transplanted cSCC mouse model was established using cells from a UVR-induced cSCC mouse model. The immunostimulatory effects of RSQ-gel were assessed by analyzing the expression of the activation marker CD86 on plasmacytoid dendritic cells (pDC) and cross-presenting conventional type I dendritic cells (XCR1⁺ cDC1) via flow cytometry. Tumor growth and survival outcomes were evaluated for RSQ-gel as monotherapy and in combination with AFL.

RSQ-gel was associated with activation of pDCs and XCR1⁺ cDC1s in the tumor-draining lymph node, as indicated by higher expression of CD86 compared to IMQ (P< 0.0001, P = 0.00175, respectively). RSQ-gel monotherapy delayed tumor growth but did not prolong survival (P = 0.0651). However, combining RSQ-gel with AFL resulted in prolonged survival compared to AFL-treated and untreated mice (P = 0.0153, P = 0.0214, respectively). Weekly RSQ-gel treatment induced comparable efficacy to daily topical IMQ treatment.

RSQ-gel with AFL demonstrated significant antitumor efficacy in the cSCC mouse model. Local RSQ-gel combined with adjuvant AFL may offer a promising therapeutic approach for cSCC.

This study explores the genetic basis of membranous nephropathy (MN) in gastric adenocarcinoma (GC) through bioinformatics and machine learning analyses.

Gene expression profiles from MN (GSE108109) and GC (GSE54129) datasets were obtained from the Gene Expression Omnibus. Common differentially expressed genes (DEGs) were identified using the limma R package. Biological functions were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways with the Cluster Profiler package. LASSO regression and Random Forest algorithms were used to identify hub genes associated with GC-related MN. The area under the curve (AUC) of ROC analysis validated these genes for their diagnostic potential. Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis were conducted, with hub genes validated through immunohistochemistry on renal and gastric cancer tissues.

We identified 40 common DEGs between GC and MN datasets. Using protein-protein interaction networks, 20 significant hub genes were selected, primarily involved in inflammatory and immune response regulation. Key hub genes identified were CCND1, CEBPD, COL10A1, and BMP2, which demonstrated high accuracy in discriminating MN. Notably, CCND1, CEBPD, and BMP2 were significantly overexpressed in glomerular and gastric cancer tissues.

Our findings highlight the crucial roles of CCND1, CEBPD, and BMP2 in the pathogenesis of GC-associated MN, providing insights for future research and potential therapeutic strategies.

Neoantigens have emerged as promising targets for personalized cancer immunotherapy due to their tumor-specific immunogenicity. However, current neoantigen prediction methods relying on combined DNA/RNA sequencing are costly and time-consuming, limiting clinical applicability. This study aimed to establish a streamlined neoantigen identification pipeline using RNA sequencing alone, evaluating its efficacy in breast and lung cancer models.

We conducted neoantigen profiling of human and mice cancers using an in silico prediction pipeline based only on RNA sequencing. We also performed neoantigen-specific T responses experiments using autologous BMDCs and PBMCs with the predicted neoantigen peptides, and ultimately demonstrating significant antitumor efficacy in murine models through in vivo therapeutic evaluation.

We identified neoantigens in mice breast cancer cell 4T1, lung cancer cell LLC and one breast cancer patient based only on RNA sequencing. In vitro experiments demonstrated that these neoantigens triggered specific T-cell responses in BALB/c mice and the patient. Mechanistic studies revealed an increased proportion of CD3+/CD137+ T cells in the RNA-derived neoantigen peptide group, with significant infiltration of CD3+/CD137+ T cells into tumor tissues.

RNA sequencing alone enables efficient neoantigen prediction and vaccine design, and the neoantigen vaccine can elicit an antitumor reaction against mouse breast cancer and lung cancer. The study showed that neoantigen prediction using RNA sequencing alone holds promise as a novel immunotherapeutic approach for cancer patients.

Adoptive T cell therapy has transformed cancer treatment, with chimeric antigen receptor (CAR) T cell therapy demonstrating remarkable clinical success in hematological malignancies. By genetically engineering a patient's own T cells to recognize and attack cancer cells, CAR T therapy has achieved durable remissions in several blood cancers. However, its efficacy in solid tumors remains limited, largely due to the immunosuppressive tumor microenvironment (TME), which impairs T cell infiltration, persistence, and function. To address these challenges, innovative strategies are being developed to reprogram T cell signaling within the hostile TME. One promising class involves chimeric non-antigen receptors (CNARs), which modulate T cell activity independently of direct antigen recognition. Among these, chimeric switch receptors (CSRs) convert inhibitory checkpoint signals into activating cues, while inverted cytokine receptors (ICRs) redirect suppressive cytokine signals to promote T cell activation. In this review, we provide a focused overview of the design principles, mechanistic functions, and therapeutic potentials of CSRs and ICRs as adjuncts to CAR T therapy in solid tumors. We also discuss key considerations regarding safety, specificity, and clinical translation to inform future advancements in engineered receptor strategies for cancer immunotherapy.

Small cell carcinoma of the esophagus (SCCE) is a rare and highly aggressive malignancy with limited therapeutic options and poor prognosis. The paucity of clinical specimens and lack of established experimental models have hindered a comprehensive understanding of its cellular heterogeneity and tumor microenvironment.

We performed single-cell RNA sequencing on SCCE samples, and integrated them with publicly available scRNA-seq datasets from esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and adjacent normal tissues (NT) from ESCC and EAC cases. An integrative transcriptomic analysis was conducted to identify cell types, infer malignant states, reconstruct differentiation trajectories, evaluate immune landscapes, and investigate fibroblast subtypes and cell-cell communication networks.

SCCE tumors were characterized by a predominance of malignant epithelial cells and exhibited a profoundly immunosuppressed phenotype, with reduced immune infiltration and widespread downregulation of immune checkpoint genes. Malignant epithelial cells showed pronounced chromosomal instability and were classified into three transcriptionally distinct subtypes with divergent differentiation trajectories. The tumor microenvironment featured a complex stromal compartment, with enrichment of extracellular matrix fibroblasts (eCAFs) characterized by elevated ELF3 regulatory activity, and collagen-driven signaling predominantly mediated by inflammatory CAFs (iCAFs). SCCE also showed the most intricate cell-cell communication network among esophageal cancer subtypes.

Our single-cell atlas offers a detailed view of the cellular heterogeneity and microenvironmental complexity of SCCE, highlighting its distinct tumor architecture, immune exclusion, and stromal reprogramming. These findings provide a valuable resource for understanding SCCE biology and form a basis for future mechanistic and exploratory biological investigations.