International braz j urol : official journal of the Brazilian Society of UrologyNaiwen Chen, Lichen Chen, Jinming Cai, Mingyue Tan, Dongliang Xu
INTRODUCTION: Radical cystectomy (RC) is the standard therapy for muscle-invasive bladder cancer (MIBC) and refractory high-risk non-muscle-invasive bladder cancer (1-3). Single-port robot-assisted radical cystectomy (RARC) offers notable minimally invasive advantages (4-6), whereas conventional transperitoneal approaches are associated with intestinal and gastrointestinal complications (7). This study evaluated an optimized extraperitoneal single-port RARC with orthotopic neobladder reconstruction for improved surgical safety and clinical outcomes. MATERIALS AND METHODS: A 57-year-old male presented with three months of intermittent painless gross hematuria. Pelvic CT revealed a bladder mass. Preoperative biopsy confirmed high-grade urothelial carcinoma with muscularis propria invasion, and the patient received gemcitabine-cisplatin neoadjuvant chemotherapy before radical surgery. Preoperative MRI identified a 3.2×2.9×2.6 cm bladder lesion without extravesical invasion or lymphadenopathy. During the procedure, the patient was placed in a supine position with buttocks elevated. A 5-cm infraumbilical single incision was made for da Vinci Xi-assisted extraperitoneal RARC, and a single-port multichannel device was deployed through the incision. Robotic instruments including a 30° endoscope, monopolar scissors, bipolar forceps, and a robotic stapler were arranged in a chopstick configuration. Via the extraperitoneal approach, we mobilized the bilateral ureters, bilateral vas deferens, and umbilical artery, dissected the bladder lateral ligaments with vascular ligation, and established a sufficient extraperitoneal working space. Bladder and prostate dissection was performed along the perivesical avascular plane, with careful protection and precise hemostasis of the dorsal venous complex. Standard pelvic lymphadenectomy was concurrently conducted during radical resection of the bladder and prostate (8). A segment of ileum was then harvested to construct an orthotopic neobladder (9), followed by anastomosis with the bilateral ureters and urethral stump. RESULTS: Operative time was 400 minutes with 200 mL blood loss and no transfusion. No perioperative complications occurred, and the patient was discharged on postoperative day 6. Pathological diagnosis was pT2aN0M0 with negative surgical margins and negative lymph nodes. The 12-month follow-up showed no tumor recurrence, normal renal function, complete daytime continence, and mild nocturnal incontinence requiring one nightly pad. CONCLUSIONS: Extraperitoneal single-port RARC with orthotopic neobladder reconstruction is a feasible minimally invasive procedure for MIBC. The optimized infraumbilical single-incision technique preserves peritoneal integrity and avoids intestinal mobilization, effectively reducing abdominal complications. It achieves reliable oncological results and improves patients' postoperative continence and quality of life.
International braz j urol : official journal of the Brazilian Society of UrologyMarcos Tobias-Machado, Ricardo C Brianson, John Eder Gamarra Bravo, Alcedir Raiser, Eliney Faria
INTRODUCTION: Horseshoe kidney is an uncommon congenital fusion anomaly that can make renal tumor surgery especially challenging because of altered rotation, limited mobility, variable vascular supply, and an unpredictable collecting system (1-7). This video presents a robot-assisted partial nephrectomy for a high-complexity renal tumor in this setting. CASE PRESENTATION: A 33-year-old man, with ECOG 0 and no relevant comorbidities, was diagnosed with a 7.5-cm solid renal mass in the central posterior portion of the left moiety of a horseshoe kidney. The lesion had a RENAL score of 10p. Contrast-enhanced computed tomography and three-dimensional reconstruction were used to understand the relationship between the tumor, aberrant vessels, renal hilum, and collecting system, supporting the decision to attempt nephron-sparing surgery (5, 8). Surgical technique and results: The procedure was performed through a transperitoneal robotic approach with the patient in right lateral decubitus using the Da Vinci Si platform. Port placement followed a standard renal robotic configuration, with a paramedian supraumbilical camera port, three robotic working ports along a craniocaudal lateral axis, a caudal fourth-arm port, and two medial assistant ports for suction, exposure, and support during renorrhaphy. After exposure of the horseshoe kidney and left hilar dissection, two arterial branches and one renal vein were identified. Tumor excision was performed under vascular control, with 20 minutes of warm ischemia and no collecting system opening, followed by two-layer absorbable renorrhaphy with adjunctive hemostatic agents. The operative time was 150 minutes. No transfusion, conversion, drain placement, or relevant immediate complication occurred. The urinary catheter was removed after 24 hours, and the patient was discharged 72 hours after surgery. Pathology showed clear cell renal cell carcinoma, Fuhrman grade 3, pT2N0M0, with negative surgical margins. During 12 months of oncologic follow-up, renal function remained stable and semiannual imaging showed no evidence of recurrence. Contemporary video reports have also emphasized the feasibility of advanced robotic renal surgery and complex partial nephrectomy strategies in selected patients (9, 10). CONCLUSION: In a carefully selected patient, robot-assisted partial nephrectomy supported by three-dimensional planning was feasible for a complex renal tumor in a horseshoe kidney, with negative surgical margins, preserved renal function, and no recurrence during 12 months of follow-up.
Cancer biology & therapyJolanta Kryczka, Jakub Mateusz Kryczka, Łukasz Janczewski, Sho Shimida, Andrzej Frączyk, Beata Kolesińska, Joanna Boncela, Ewa Brzeziańska-Lasota
BACKGROUND: Lung cancer presents complex etiopathology involving a mix of genetic predispositions and environmental factors. The best treatment modality is surgical resection. However, it becomes ineffective in the advanced metastatic stage. Thus, cisplatin-based chemotherapy, though restricted by an intrinsic and/or acquired chemo-resistant phenotype, remains the first-line therapy for advanced non-small-cell cancer (NSCLC). METHODS: Various tools were used to verify the mRNA expression and protein levels of ABC and ALDH proteins in patient-derived non-small-cell lung cancer (NSCLC) samples (GSE102287, GSE43580) and cell lines A549 and NCI-H158 (including their respective cisplatin-resistant variants) to verify the cisplatin-sensitizing abilities of newly synthesized bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide-non-toxic ALDH and ABCC2 inhibitors. RESULTS: We identified significant molecular differences in the expression levels of ABCC1, ABCC5, ABCC3, ALDH7A1, and ALDH3A1. Additionally, a fairly significant patient subgroup (Z-score > 1.5), characterized by ABCC2 and ALDH3A1 overexpression, was identified. Importantly, in vitro, ABCC2 and ALDH3A1 accompany the acquisition of cisplatin resistance in A549 cells. Bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide reverses cisplatin resistance in a cisplatin-resistant variant of A549 cells (via ALDH and ABCC2 inhibition) but not in NCI-H158 cells. CONCLUSIONS: Molecular categorization of NSCLC cancer is essential for predicting therapy outcomes, enabling the use of bis-(di-4-phenyl-benzylaminethiocarbonyl)disulfide as a cisplatin therapy enhancer for NSCLC patients' subpopulation with significant ABCC2 and ALDH3A1 overexpression.
Myasthenia gravis (MG) is a complex autoimmune neuromuscular disorder, and the role of lipid metabolism dysregulation in MG pathogenesis remains unclear. This study aimed to investigate the molecular mechanisms of lipid metabolism regulation in myasthenia gravis development by integrating single-cell and bulk transcriptomic data. This study analyzed bulk RNA sequencing data from the GSE85452 dataset (13 MG patients and 12 healthy controls) and single-cell RNA sequencing data from the GSE227835 dataset (10 MG patients and 10 healthy controls). Differential expression analysis was performed, and weighted gene co-expression network analysis (WGCNA) was conducted to identify disease-related modules. Key genes were screened through the intersection of differentially expressed genes (DEGs), WGCNA hub genes, and lipid metabolism-related genes. Functional enrichment analysis, protein‒protein interaction (PPI) network construction, immune infiltration analysis, and regulatory network analysis were performed. Single-cell analysis was used to characterize cellular heterogeneity and intercellular communication features. A nomogram prediction model was constructed and internally validated using leave-one-out cross-validation (LOOCV). Potential therapeutic compounds were identified through drug prediction and molecular docking analysis. Furthermore, key genes were validated by RT-qPCR in an independent cohort of 5 MG patients and 5 healthy controls. A total of 823 DEGs and 13 co-expression modules were identified, of which 4 modules were significantly associated with MG. Twenty-one candidate genes were screened, and 2 key genes (IRS2 and ALDH2) were ultimately determined. IRS2 was significantly downregulated while ALDH2 was significantly upregulated in MG patients. The nomogram model based on key genes demonstrated excellent predictive performance (AUC = 0.897). Immune infiltration analysis showed increased regulatory T cells (Tregs) and decreased CD4+ memory activated T cells in MG patients. Single-cell analysis identified 10 major cell types. Cell‒cell communication analysis revealed dense interactions among CD4+ T cells, B cells, and CD14+ monocytes. Drug prediction identified metformin and cyclophosphamide as potential therapeutic candidates, and molecular docking confirmed favorable binding affinities. This integrative study generated the hypothesis that lipid metabolism dysregulation, potentially mediated by IRS2 and ALDH2, may contribute to immune dysfunction in MG pathogenesis. These findings provide preliminary insights into the molecular mechanisms underlying MG development and suggest potential diagnostic biomarkers and therapeutic targets. However, these results are hypothesis-generating, and clinical translation is contingent upon rigorous mechanistic validation through functional experiments, animal models, and larger multicenter clinical cohorts.
The aging male : the official journal of the International Society for the Study of the Aging MaleMingshun Zuo, Yuanjian Liao, Qiang Xu, Ailing Su, Ni Fu, Chenghong Zou
BACKGROUND: Observational studies link hyperthyroidism to increased prostate cancer (PCa) risk, but causality and mechanisms remain unclear. Graves' disease (GD), the primary cause of hyperthyroidism, involves chronic immune dysregulation that may influence PCa through shared immune pathways. METHODS: We performed bidirectional two-sample Mendelian randomization (MR) using IEU Open GWAS data, then integrated differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning on Gene Expression Omnibus (GEO) datasets to identify shared gene, validated by ROC curves, and analyzed immune profilesusing ssGSEA. RESULTS: MR analysis indicated that genetic predisposition to GD significantly reduced PCa risk (OR = 0.997, 95% CI = 0.996-0.999, p = 0.004), with consistentsensitivity and no reverse causality. Four key genes (BTG2, JUN, JUNB, FOS) were identified as robust shared genes with high predictive accuracy in external validation. Immune profiles analysis revealed disease-specific associations of these genes: BTG2 and JUNB correlated with memory CD8 T cells in GD, whereas all four genes correlated with dendritic cells, mast cells and NK cells in PCa. CONCLUSION: This study provided novel insights into the protective effect of GD against PCa and identified shared genes and immune mechanisms, offering a deeper understanding of the common mechanisms between GD and PCa.
The gut microbiome is increasingly recognized as a key modulator of cancer immunotherapy efficacy. Given that diet is one of the most important determinants of the gut microbiome composition and function, nutritional strategies have emerged as promising tools to modulate anti-tumor immune responses. Here, we demonstrate that dietary supplementation with inulin reduces tumor growth and enhances αPD-1 efficacy in mice. These effects were associated with increased frequencies of intra-tumoral CD8⁺ and CD4⁺ T cells, particularly CCR9⁺CXCR3⁺ subsets, and enrichment of beneficial taxa such as Akkermansia and Lachnospiraceae, alongside elevated short-chain fatty acids (SCFA) levels. Among the SCFA, butyrate alone recapitulated the anti-tumor effect of inulin and had an additive effect when combined with αPD-1 therapy in a CD8⁺ T cell-dependent manner. Butyrate exerted its anti-tumor effects by transcriptional changes in CD8⁺ T cells involving activation of proliferation, trafficking, and metabolic pathways. In a cohort of 117 non-small cell lung cancer (NSCLC) patients amenable to immunotherapy, the median dietary fiber intake was lower than previously published studies but correlated with enrichment of Faecalibacterium praunitzii and metabolic pathways related to sucrose degradation and tryptophan biosynthesis. Collectively, our findings highlight the therapeutic potential of targeting diet-microbiome-immune system interactions to improve cancer immunotherapy outcomes.
Cancer biology & therapyYaqiong Jie, Zhongyu Lu, Xiaoxuan Wang, Dongsheng Chen, Xing Zhang, Xinguang Han
BACKGROUND: This study aimed to systematically characterize the genomic alteration landscape of phosphatidylinositol 4-kinase (PI4K) and phosphatidylinositol phosphate kinase (PIPK) family genes in solid tumors, assess the correlation of these alterations with patient clinical outcomes and the tumor immune microenvironment, and explore their potential as novel biomarkers or therapeutic targets. METHODS: A retrospective analysis was conducted on whole-exome sequencing data from a cohort of 2,144 Chinese patients encompassing 18 solid tumor types. Genomic and transcriptomic data from The Cancer Genome Atlas (TCGA) pan-cancer project were integrated to perform survival analysis, correlating genomic alterations, gene expression levels, and patient overall survival. Associations between these gene alterations and tumor mutational burden (TMB), microsatellite instability (MSI), and levels of tumor-infiltrating immune cells were also evaluated. RESULTS: We identified PI4K/PIPK alterations in 10.5% of 2,144 patients, with PIP4K2C amplification reaching 48%. While PI4K2B amplification and overexpression are consistently associated with poor prognosis in COAD, family-wide effects were highly heterogeneous across cancers. Alterations significantly correlated with higher TMB and MSI-H, and multi-omics analysis revealed tissue-specific immune landscapes, highlighting the family's potential for risk stratification and immunotherapy. CONCLUSIONS: This study provides the first systematic delineation of the genomic alteration landscape of PI4K and PIPK families at a pan-cancer scale within a Chinese population. It identifies PI4K2B as an amplification-driven prognostic biomarker in colorectal cancer, with potential clinical value analogous to HER2. These findings illuminate the significant roles of these kinases in cancer and provide novel insights for future precision oncology strategies.
Redox report : communications in free radical researchYifan Ma, Simeng Zhang, Dongyang Zhang, Zhongyan Hua, Zhijie Li
OBJECTIVES: Neuroblastoma (NB) is a common pediatric extracranial solid tumor. Dimethylaminomicheliolide (DMAMCL), a prodrug of Micheliolide (MCL), shows antitumor activity against NB, but its mechanisms remain unclear. This study investigated the antitumor mechanisms of DMAMCL in NB. METHODS: Key pathways/genes were identified by RNA-seq and ferroptosis PCR array. Ferroptosis was confirmed by indicators. Mechanisms were investigated using siRNAs, shRNAs, and overexpression plasmids in vitro and in vivo. Direct targets were screened by LiP-MS. Molecular biology experiments elucidated the mechanisms. RESULTS: DMAMCL induced ferroptosis in NB in vitro and in vivo, upregulating HMOX1. HMOX1 knockdown attenuated DMAMCL-induced ferroptosis and its overexpression triggered ferroptosis in MYCN-amplified NB cells but not in MYCN-nonamplified cells. DMAMCL-induced ferroptosis via HMOX1 upregulation depended on MYCN levels. Mechanistically, DMAMCL bound to KEAP1 in MYCN-amplified NB cells, increasing nuclear NRF2 and upregulating HMOX1. In MYCN-nonamplified NB cells, DMAMCL upregulated STEAP3, increasing Fe2+ and lipid peroxidation to induce ferroptosis. STEAP3 overexpression induced ferroptosis and suppressed tumor growth. DISSCUSION: DMAMCL induces ferroptosis in NB through MYCN-associated dual pathways, activating the NRF2/HMOX1 axis via KEAP1 binding in MYCN-amplified cells, while upregulating STEAP3 in MYCN-nonamplified cells. This provides new insights for DMAMCL application in treating NB subtypes with different MYCN levels.
Hematology (Amsterdam, Netherlands)Abdullah M Alrajhi, Bashayer Alshehri, Walaa A Alshahrani, Arwa AlHaj Issa, Amal H Alotaibi, Areej Abumustafa, Ghadah Alyousif, Nora Alkhudair, Mai Alalawi, Na…
OBJECTIVE: Hodgkin lymphoma (HL) constitutes 3.4% of all cancers in Saudi Arabia, with advanced-stage relapse rates reaching 40%. While the anti-CD30 agent brentuximab vedotin (BV) has established efficacy, local data are limited. This study aims to assess the real-world effectiveness and safety of Brentuximab vedotin (BV)-containing regimens compared to non-BV regimens in relapsed or refractory classical Hodgkin lymphoma (cHL) in Saudi Arabia. METHODS: A retrospective, multicenter cohort study was conducted including 93 adult patients with relapsed or refractory cHL in Saudi Arabia between 2016 and 2021. Patients were categorized into a BV-containing group (n = 61) and a control group (n = 32). The outcomes were overall response rate (ORR), complete response (CR), event-free survival (EFS), and post-chemotherapy complications. RESULTS: = The BV group showed a higher ORR compared to the non-BV group (82.5% vs. 76.9%), although this difference was not statistically significant (adjusted odds ratio [aOR] = 9.09; 95% CI = 0.67-122.57; P = 0.10). CR rates were comparable between the two groups, at 59.6% in the BV group vs. 61.5% in the control group (aOR = 1.86; 95% CI = 0.24-14.46; P = 0.55). EFS was significantly longer in the BV group compared with the control group in the crude analysis (22.5 vs. 11.2 months; P = 0.03); however, this finding did not reach statistical significance in the regression analysis (beta coefficient = 7.04; 95% CI = -2.96 to 17.03; P = 0.18). Post-chemotherapy complications were comparable and not statistically significant across both groups. CONCLUSION: The research indicates that BV may offer a potential clinical advantage for patients with relapsed or refractory cHL. To validate these findings and optimize treatment strategies for this population, larger long-term studies with expanded patient cohorts are required.
OncoimmunologyShuhang Xu, Yaorong Su, Senmin Zhang, Dongye Huang, Song Wu, Cailu Song, Wenhuan Zhong, Lan Xie, Wenkuan Chen
Metastasis is a major determinant of treatment failure and mortality in thyroid cancer, yet the interplay between malignant evolution and the immune microenvironment remains poorly characterized. Immunotherapy offers promise, but its efficacy requires a deeper understanding of tumor-associated immune infiltration and checkpoint regulation. In this study, we constructed a high-resolution transcriptomic atlas of the thyroid cancer ecosystem by analyzing 55,005 single cells from paired primary tumors and lymph node metastases. By integrating chromosomal copy number variation (CNV) inference with consensus nonnegative matrix factorization (cNMF), we deciphered the intrinsic heterogeneity of malignant epithelial cells, revealing distinct transcriptional programs and developmental trajectories driving the metastatic cascade. The metastatic niche exhibited significant reprogramming of the immunosuppressive landscape, characterized by the enrichment of FOXP3⁺ regulatory T (Treg) cells, LAMP3⁺ dendritic cells (DCs), and CCL18⁺ M2-like macrophages. Notably, while canonical checkpoints PD-1 and PD-L1/2 showed minimal expression, ligand-receptor interaction analysis identified the LAG3-LGALS3 axes as dominant immune evasion pathways mediating the crosstalk between CD8⁺ T cells and the tumor stroma. In conclusion, this study comprehensively maps the coevolution of malignant thyrocyte plasticity and the immunosuppressive metastatic niche. By uncovering the specific role of LAMP3⁺ DCs and identifying LAG3/TIGIT as critical alternative checkpoints, our findings challenge the utility of conventional PD-1 blockade in this context and provide a robust molecular rationale for developing next-generation immunotherapeutic strategies tailored to thyroid cancer. Although limited by a modest sample size, these findings provide a foundation for further investigation of the metastatic immune landscape in thyroid cancer.
OncoimmunologySabina Niyazova, Christine Sers, Hendrik Bläker, David Horst, Wolfgang Schmitt, Zehra Karadeniz, Simon Schallenberg, Alexej Ballhausen, Dominik P Modest, Colin…
Early-stage colorectal cancer (CRC) with confirmed microsatellite instability generally has a favorable prognosis associated with pronounced immune infiltration. However, some patients still develop metastases. The underlying mechanisms, particularly those related to the tumor immune microenvironment, remain incompletely understood. The study included tissue samples from 217 patients with dMMR/MSI-H CRC, comprising 89 stage III/IV and 128 stage I/II cases. Tissue microarrays and immunohistochemical analyzes were performed for all cases. We evaluated immune markers identifying T cells, B cells, dendritic cells, natural killer cells, macrophages, immunosuppressive markers, and immune checkpoint targets in epithelial and stromal compartments, and additionally performed a cohort-derived immune infiltration score (IIS). The survival analysis assessed the prognostic impact of immune markers stratified by tumor stage. Stage I/II dMMR/MSI-H CRCs showed significantly higher CD3⁺ T-cell and natural killer cell levels, higher IIS metrics across all regions, and higher CD4⁺ T helper cell levels in the stroma. Stage III/IV cases exhibited increased epithelial expression of indoleamine 2,3-dioxygenase 1. Given the limited number of stage IV patients, an additional stage III vs. stage I/II comparison was performed, revealing that these immune differences were already evident at the level of nodal progression. In addition, CD3⁺, CD4⁺, and CD8⁺ T cells and the IIS showed varying prognostic associations across tumor stages. These findings suggest that the overall immunogenicity and prognostic relevance of immune markers in dMMR/MSI-H CRC depend on tumor stage. Immune profiling could be used for early-stage patient stratification and also suggests the potential benefit of early immunotherapeutic intervention.
Hematology (Amsterdam, Netherlands)Sufei Kuang, Qixin Liu
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) presents a complex etiology and challenging diagnosis. This study aims to investigate potential pathogenic genes. METHODS: We identified DLBCL risk genes (DRGs) through expression quantitative trait loci-Mendelian randomization (eQTL-MR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to explore biological functions. Single-cell RNA sequencing (scRNA-seq) data were analyzed to delineate the subcellular localization. Immune infiltration analyses examined the role of genes in the DLBCL immune microenvironment. Finally, drug sensitivity analyses were performed to predict potentially sensitive drugs. RESULTS: Following eQTL-MR and prognostic analyses, we identified 15 genes associated with both the pathogenesis and prognosis of DLBCL. These genes were successfully integrated into a risk gene model, achieving an Area Under the Curve (AUC) of 0.787. GO and KEGG enrichment analyses of genes localized significant pathways, including NF-κB signal transduction. ScRNA-seq analysis suggested that DRGs may be linked to the immune microenvironment of DLBCL. Further immune infiltration analysis confirmed the pivotal role of immune infiltration in the malignant progression of DLBCL. CONCLUSION: This study unveils 15 risk genes as potential pathogenic and therapeutic biomarkers for DLBCL. These findings provide novel insights and targets for understanding the pathogenesis, diagnosis, and treatment of DLBCL.
Gut microbesLucía Serrano-García, Elisabeth Martínez-Salvador, Ana Belda-Marco, Clara Herrero-Oliva, Javier Cortés, Antonio Llombart-Cussac, Leonor Fernández-Murga
Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype for which immune checkpoint inhibitors combined with chemotherapy have improved outcomes in selected patients. However, primary and acquired resistance remain common, underscoring the need to identify extrinsic, modifiable determinants of antitumor immunity. Increasing evidence indicates that the gut and tumor-associated microbiota shape systemic and intratumoral immune tone and influence the efficacy of cancer therapies. Beyond microbial composition, microbiota-derived metabolites-including short-chain fatty acids, indole-tryptophan derivatives, bile acids, polyamines, and other small molecules-can act as functional mediators linking microbial ecology to immune-cell programming and tumor biology. These metabolites modulate dendritic cell function, T-cell priming and fitness, myeloid polarization, inflammatory set points, and metabolic pathways within the tumor microenvironment, thereby potentially enhancing or constraining responses to chemoimmunotherapy. Importantly, while some studies propose intratumoral microbial effects, most clinically actionable evidence currently supports systemic gut-derived metabolites and immune tone modulation that secondarily shapes the TNBC tumor microenvironment. In this review, we synthesize current knowledge on (i) the immunobiology of triple-negative breast cancer (TNBC) relevant to microbiota-driven modulation, (ii) mammary and gut microbiome features reported in TNBC, and (iii) mechanistic pathways through which microbial metabolites may regulate antitumor immunity and immune checkpoint inhibitors (ICI) sensitivity. We also discuss methodological considerations for integrating microbiome profiling with metabolomics and immune phenotyping and evaluate emerging opportunities to leverage microbiota-derived metabolites as biomarkers and therapeutic targets. Finally, we highlight translational strategies-including diet, pre/probiotics, antibiotic stewardship, fecal microbiota transplantation, and metabolite-centric ("postbiotic") approaches-and outline priorities for TNBC-focused, prospective multi-omics studies to move from associative signatures toward actionable interventions.
OncoimmunologyLorenzo Falchi, Martin Hutchings, David Tybor, Junhua Yu, Abualbishr Alshreef, Anthony Wang, Kavita Sail, Zhijie Ding, Alex Mutebi, Poliana Patah, Nisha Kishor…
Patients with relapsed/refractory follicular lymphoma (R/R FL) often experience multiple disease recurrences with progressively shorter duration of remission. Chemoimmunotherapy (CIT) is commonly used for R/R FL in second-line and later settings but is not curative; novel, improved treatments are needed. Epcoritamab, a CD3 × CD20 bispecific antibody, is approved as monotherapy for R/R FL after ≥ 2 lines of therapy (LOTs) and combined with lenalidomide and rituximab (R2) for R/R FL. Epcoritamab + R2 pivotal data demonstrated superiority over R2, but no comparison of epcoritamab + R2 versus CIT exists. Therefore, we conducted an adjusted comparative analysis of epcoritamab + R2 from arm 2 of the phase 1b/2 EPCORE NHL-2 trial (NCT04663347; n = 111; US, 23.4%) versus R2/CIT using COTA individual patient-level electronic health records (n = 380; US, 100%) of patients with R/R FL after ≥ 1 previous LOT. Epcoritamab + R2 improved response rates over R2/CIT (overall response, 96.9% versus 80.5%, P < .001; complete response, 90.2% versus 55.1%, P < .001). Epcoritamab + R2 improved duration of response (HR, 0.29 [95% CI, 0.18-0.47]; P < .001), duration of complete response (HR, 0.31 [95% CI, 0.17-0.55]; P < .001), progression-free survival (HR, 0.43 [95% CI, 0.28-0.68]; P < .001), and overall survival (HR, 0.33 [95% CI, 0.16-0.70]; P = .003) over R2/CIT. These findings support epcoritamab + R2 as a promising chemotherapy-free treatment option for R/R FL.
Cancer biology & therapyMengting Luo, Feng Shen, Wanli Xu, Christopher Corpe, Jin Wang
Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies and has an extremely poor prognosis. Its progression is largely driven by a highly complex and immunosuppressive tumor microenvironment (TME), highlighting the urgent need for a deeper understanding of its molecular mechanisms. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided unprecedented opportunities to dissect cellular heterogeneity, spatial organization, and gene expression dynamics within the TME. In this review, we summarize the major scRNA-seq and ST technologies and their unique strengths in cancer research and highlight their integrated applications in revealing PDAC heterogeneity, stromal-immune interactions, and mechanisms of therapeutic resistance. We further discuss how these approaches can inform biomarker discovery and guide the development of novel therapeutic strategies. Together, these findings suggest that integrated single-cell and spatial transcriptomics offers transformative potential to advance precision oncology and improve outcomes for patients with pancreatic cancer.
Gut microbesDominik Awad, Holly Attebury, Ryan Hong, Kwi Kim, Li Zhang, Allison Bischoff, Sajan Achi, Aaron denDekker, Nick Lesniak, Stephanie The, Joseph A Nieto Carrion,…
Pancreatic ductal adenocarcinoma has a unique tumor microbiome, and the depletion of gut bacteria or fungi using antibiotic/antifungal cocktails has been shown to decrease pancreatic tumor burden in mice. However, functional studies evaluating the role of tumor-associated microbes are few due to the limited availability of clinically relevant microbiota. Here, we describe in detail an effective workflow for the isolation of bacteria and fungi from the duodenum and tumor of pancreatic cancer patients, specifically optimized for cryopreserved, low biomass samples. Using this workflow we also isolated microbiota from normal pancreatic tissue and duodenum from organ donors, and we confirmed the presence of bacteria and fungi isolated from tissue samples with 16S and ITS sequencing analysis. Isolation and sequencing results show distinct similarities between the pancreatic and duodenal microbiomes and highlight unique bacterial strains that survive in the tumor microenvironment. As a proof of concept, we characterized a select Klebsiella oxytoca strain (UMKO1) isolated from a pancreatic tumor, using whole genome sequencing, metabolomics, and ex- vivo tumor cultures to determine its potential impact on the pancreatic tumor microenvironment. In summary, this optimized workflow allows for the isolation of a variety of bacteria and fungi from low biomass, cryopreserved pancreatic and duodenal tissues, which can then be used for functional studies characterizing clinically relevant tumor-associated microbiota.
OncoimmunologyTithi Ghosh Halder, Erin Kelley, Jorge Soria-Bustos, Trason Thode, Serina Ng, Taylor Bargenquast, Alexis Weston, Ryan Rodriguez Del Villar, Mohan Kaadige, Erku…
Tumor-infiltrating lymphocyte (TIL) therapy, which involves extracting, expanding, and reinfusing immune cells to target cancer cells, has shown promise in melanoma treatment, but requires optimization for broader efficacy. The success of TIL therapy depends on the recognition of tumor-associated antigens, but neoantigen-reactive T-cells are often rare and exhausted in less immunogenic malignancies. Isolating T cells enriched in neoantigen reactivity prior to in vitro expansion and reinfusion may improve the response rates. To this end, our proprietary Specific Neo-Antigen Peptides (SNAP™) technology platform improves the accuracy of neoantigen prediction and validation by combining advanced computational modelling and PepSeq, a high-throughput screen for the physical credentialing of putative neoantigens based on their affinity to bind patient-specific HLA class II proteins. This approach allows for the education and enrichment of TILs (SNAP-TILs) with personalized, predefined, highly immunogenic neoantigens prior to expansion. Using the SNAP platform, we consistently achieved, on average, a SNAP-TIL product comprising 96% CD3+ cells, with a mixture of 75% effector and 23% central memory cells. SNAP-TILs exhibited greater efficacy and selectivity in immune infiltration than TIL, which was expanded by the rapid expansion protocol alone using ex vivo models. SNAP-TIL was also reactive in highly and poorly immunogenic tumors, with 70% and 50% tumor growth inhibition in melanoma and pancreatic patient-derived xenograft models, respectively. This study demonstrates the novel benefit of our Personalized Neoantigen Pipeline approach, potentially providing a durable antitumor immune response for a larger proportion of cancer patients.
Global public healthKallin C Hermann, Alejandro Andrés Peralta Chiriboga, Kevin T Fuji, Anne L O'Keefe, María Sol Jurado Vaca, Abubakar Tauseef, Karina Kletscher, Jason Beste
Human papillomavirus (HPV) is estimated to cause 99.7% of all cervical cancers and is the main cause of anal cancer. Despite global progress, Ecuador has one of the highest cervical cancer mortality rates in Latin America, with fluctuating vaccine uptake since its introduction for girls in 2014 and expansion to boys in 2024. Semi-structured interviews were conducted with parents of vaccine-eligible children and healthcare providers (HCPs) in Quito. The interviews explored HPV knowledge, perceptions, and access to vaccination. The transcripts were analysed thematically. Forty-one participants (32 parents, 9 HCPs) were interviewed. Eight themes emerged: (1) parents desire more information about HPV, (2) neither parents nor HCPs associate HPV with cancer in men, (3) mothers have more knowledge than fathers, (4) fear of side effects contributes to vaccine hesitancy, (5) fear of sexual promiscuity does not influence vaccination, (6) HPV vaccine administration is conducted at schools, but parents and providers desire better support from these schools, (7) parents perceive a lack of information as their greatest barrier, while HCPs perceive carelessness among parents, and (8) age guidelines for vaccination can be confusing. HPV vaccine uptake is shaped by individual and system-level barriers. Aligning provider-parent perspectives and strengthening school- and community-based education may improve vaccination.
Colorectal cancer (CRC) progression is driven by dynamic interactions among tumor cells, immune infiltrates, and the gut microbiota. While regulatory T cells (Tregs) may contribute to immune suppression in CRC, the role of non-conventional Tregs remains poorly defined. We identified a non-conventional population of microbiota-induced Tregs in the human colonic mucosa that co-expressed CD4, CD8α, CXCR6, and CCR6, termed DP8α Tregs, that exert potent immunomodulatory properties in different inflammatory settings. Their status and role in CRC, however, have not been investigated. Here, using multiparametric flow cytometry in a prospective cohort of CRC patients, we showed that DP8α Tregs are significantly enriched in tumors compared to paired non-tumoral colonic mucosa. Tumor-infiltrating DP8α Tregs displayed elevated expression of the CD39/CD73 ectonucleotidases, as well as CCR5, consistent with a suppressive phenotype within the tumor microenvironment. Functional co-culture assays further demonstrated that sorting DP8α Tregs from CRC tumors inhibited both CD4 and CD8 T-cell proliferation, an effect largely reversed by pharmacological inhibition of CD39 and CD73, which was associated with reduced IL-2 levels. Together, these findings show that DP8α Tregs enriched in the CRC tumor microenvironment, are able to suppress effector T-cell responses through the purinergic pathway and support further investigation of their contribution to immune regulation in CRC.
OncoimmunologyEsmeralda García-Torralba, Aitziber Buqué, Lorenzo Galluzzi
The clinical management of patients with breast cancer is largely dictated by tumor stage, disease subtype and (at least in some settings) specific molecular features thereof (e.g., BRCA1 mutations, PD-L1 positivity). However, not all patients with breast cancer respond to therapeutic approaches that a priori are precisely targeted to their disease. At least in part, this may reflect the fact that breast neoplasms are highly heterogeneous from a broad immunological perspective, even when they exhibit similar disease subtype and molecular features. Thus, integrating extra immunological parameters into current decision-making algorithms may considerably improve clinical management in this large patient population. In this context, circulating indicators of global immune fitness and ongoing anticancer immunity stand out as particularly promising tools for minimally invasive prognostic and/or predictive assessments. Here, we summarize and critically discuss the circulating immune landscape of human breast cancer, whenever possible comparing across disease subtypes, stages, and treatment outcomes.