bims-tumhet 2026-05-31 papers

bims-tumhet

Biomed News

on Tumor heterogeneity

Issue of 2026–05–31
eleven papers selected by
Sergio Marchini, Humanitas Research

Circulating cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) in oncology: from technological advances to clinical applications.
Pan-cancer spatial atlas of tertiary lymphoid structures.
Emerging biomarkers for the early detection of high-grade serous tubo-ovarian cancer.
Rethinking Immunity in Tissues: The Biology of Tertiary Lymphoid Structures.
HRDetect in Tubo-ovarian Carcinoma: Stratification and Therapeutic Implications.
The biological characteristics of tertiary lymphoid structures in head and neck cancer.
Spatially Resolved Molecular Subtyping Uncovers Tumor Progression and Immune Evasion Mechanisms in High-Grade Serous Ovarian Cancer.
The formation and function of tertiary lymphoid structures.
Head and Neck Cancer.
Four-year survival outcomes with dostarlimab plus chemotherapy in mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer in the RUBY trial.
Targeting claudins in cancer.

NPJ Precis Oncol. 2026 May 25.

Circulating cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq) in oncology: from technological advances to clinical applications.

Edoardo Francini, Sara Bleve, Giuseppe Nicolo Fanelli, Mara Serena Serafini, Filippo Pederzoli, Alessandra Ferri, Erika Minonne, Jacopo Venturini, Silvia Rodrigues, Hubert Pakula, Cristian Lolli, Massimo Cristofanilli, Pier Vitale Nuzzo.

Circulating cell-free DNA (cfDNA) methylation profiling enables minimally invasive cancer detection and monitoring. Among available methods, cfMeDIP-seq is a sensitive, scalable, bisulfite-free approach suitable for low-input cfDNA. This review summarizes its principles, comparative technologies, and clinical applications, including early detection, tumor classification, and minimal residual disease monitoring. Despite promising performance, challenges remain in standardization and validation, while emerging multi-omic integrations may further enhance its role in precision oncology.

DOI: https://doi.org/10.1038/s41698-026-01507-w
Science. 2026 May 28. 392(6801): eadz2742

Pan-cancer spatial atlas of tertiary lymphoid structures.

Kyung Serk Cho, Yunhe Liu, Guangsheng Pei, Jianfeng Chen, Yibo Dai, Yang Liu, Tieling Zhou, Antoine Bougouin, Alejandra Serrano, Khalida Wani, Akshaya Jadhav, Jimin Min, Sharia Hernandez, Wei Lu, Daiwei Zhang, Jiahui Jiang, Diana Shamsutdinova, Enyu Dai, Fuduan Peng, Ansam Sinjab, Paola A Guerrero, Idania Carolina Lubo Julio, Kai Yu, Helen Clark, Dipen Maru, Mingyao Li, Andrew Futreal, Sanghoon Lee, Luisa Maren Solis Soto, Lulu Shang, Pavlos Msaouel, Jaffer A Ajani, Hannah Beird, Amir A Jazaeri, Alexander J Lazar, Catherine Sautes-Fridman, Wolf H Fridman, Anirban Maitra, Humam Kadara, Jianjun Gao, Padmanee Sharma, Linghua Wang.

Tertiary lymphoid structures (TLSs) are critical regulators of antitumor immunity, yet their spatial organization, maturation, and clinical relevance remain incompletely defined across cancers. We analyzed spatial transcriptomics spanning 12 cancer types to construct a pan-cancer TLS atlas and characterized TLS spatial architecture and maturation states. TLS maturation was accompanied by coordinated remodeling of distinct niche cell populations and distance-dependent gradients in tumor programs, orthogonally supported by ultrahigh-plex single-cell spatial profiling. To enable scalable TLS profiling, we trained an artificial intelligence framework that predicts TLS maturation states directly from hematoxylin and eosin-stained images and evaluated it across TCGA and independent therapy cohorts. We further derived a maturation-aware composite score capturing intratumoral TLS state composition, which robustly stratifies patients across cancer and treatment contexts, outperforming conventional TLS metrics.

DOI: https://doi.org/10.1126/science.adz2742
Crit Rev Oncol Hematol. 2026 May 26. pii: S1040-8428(26)00276-3. [Epub ahead of print]224 105389

Emerging biomarkers for the early detection of high-grade serous tubo-ovarian cancer.

Sara Atiq, Nikola A Bowden, Kristina Warton, Michelle W Wong-Brown.

  High-grade serous tubo-ovarian cancer remains one of the deadliest gynaecological malignancies, mostly due to vague symptoms and late-stage diagnosis. This review explores the strengths and limitations of current early detection biomarkers, specifically for high-grade serous tubo-ovarian cancer. While significant progress has been made, challenges remain with low sensitivity and specificity of detection biomarkers and the need for multimodal approaches and validation in diverse populations. This review explores biomarkers with demonstrated potential for detecting early-stage high-grade serous tubo-ovarian cancer through non-invasive methods in the general population and have the potential to improve patient outcomes. To date, there is no biomarker-based screening or early diagnosis test that has been shown to reduce ovarian cancer mortality in the larger population. This review focuses on current and emerging biomarkers in high-grade serous tubo-ovarian cancer, including genomic and proteomic changes that have diagnostic potential. While there are no biomarkers that have been approved for population-wide screening, evidence strongly supports DNA methylation-based liquid biopsy approaches for screening and early detection of high-grade serous tubo-ovarian cancer. This review highlights emerging biomarkers for early detection through minimally invasive methods and underscores the challenges of existing detection biomarkers.

Keywords:  Biomarkers; DNA methylation; Early detection; Liquid biopsy; Ovarian cancer

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105389
Immunol Rev. 2026 Jul;340(1): e70135

Rethinking Immunity in Tissues: The Biology of Tertiary Lymphoid Structures.

Michelle A Linterman, Palwinder K Mander.

DOI: https://doi.org/10.1111/imr.70135
Clin Cancer Res. 2026 May 27.

HRDetect in Tubo-ovarian Carcinoma: Stratification and Therapeutic Implications.

Kalyan Banda, Helen R Davies, Yogesh Kumar, Yasin Memari, Andrea Degasperi, Marc Radke, Isabel Rodriguez, Ted A Gooley, Ronit Katz, Francesca Menghi, Thomas Harding, Kevin Lin, Edison T Liu, Serena Nik-Zainal, Elizabeth M Swisher.

PURPOSE: To evaluate HRDetect, a mutational-signature-based algorithm, for prognostic utility in tubo-ovarian carcinoma (OC), and to determine if whole-genome sequencing (WGS) with rearrangement signature (RS) analysis can refine genomic classification beyond the traditional homologous recombination deficient (HRD) versus proficient (HRP) framework.
EXPERIMENTAL DESIGN: WGS was performed on matched tumor-normal pairs from 185 patients with advanced-stage OC from the University of Washington (UW) cohort. HRDetect scores were calculated using substitution signatures, rearrangement signatures, microhomology-mediated deletions, and global loss of heterozygosity. An independent validation cohort (ARIEL2, n = 77) of platinum-sensitive OC treated with rucaparib, was analyzed to correlate HRDetect with PARP inhibitor (PARPi) response. RS analysis and unsupervised hierarchical clustering were employed to delineate genomic subgroups.
RESULTS: In the UW cohort, 51.4% of cases were classified as HRDetect-high and had significantly prolonged median overall survival versus others (6.2 vs 4.1 years; HR=0.6; 95% CI=0.41-0.87; p=0.007). 48.4% of HRDetect-high tumors harbored BRCA1/2 mutations or BRCA1 promoter methylation, while 22.1% lacked BRCA1/2 alterations. A substantial fraction (23.2%) fell into an HRDetect-intermediate category, highlighting greater genomic heterogeneity than currently appreciated. RS profiling uncovered eleven genomic clusters, with specific RS profiles (RS1, RS14, RS18) correlating with poor survival. In ARIEL2, HRDetect-high tumors showed better PARPi responses, with improved progression-free survival (11.1 vs 7.1 months; HR=0.44; 95% CI=0.26-0.74; p=0.03) and response rates (54% vs 22.5%).
CONCLUSIONS: HRDetect predicts survival and sensitivity to PARPi in OC. Combined with RS-based clustering, it reveals unappreciated genomic heterogeneity, and supports a nuanced stratification framework to improve precision oncology in OC.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1629
Front Immunol. 2026 ;17 1818962

The biological characteristics of tertiary lymphoid structures in head and neck cancer.

Suwen Bai, Yuan Wei, Fankai Liu, Hexing Sun, Xianhai Zeng, Peng Zhang.

  Head and neck cancer (HNC) is one of the most prevalent malignancies worldwide, and its clinical management remains fraught with formidable challenges. In recent years, as our understanding of the tumor microenvironment (TME) has deepened, immunotherapy-especially the clinical application of immune checkpoint inhibitors (ICIs)-has brought a revolutionary breakthrough to HNC treatment. However, only a subset of patients can derive clinical benefits from such therapies, highlighting the urgent need to identify reliable predictive biomarkers. Tertiary lymphoid structures (TLS), lymphocyte aggregates ectopically formed in non-lymphoid tissues such as chronically inflamed or tumor sites with functions analogous to secondary lymphoid organs, have emerged as a burgeoning research hotspot in tumor immunology. This review aims to systematically elaborate on the biological characteristics of TLS in HNC, their clinical value as biomarkers for prognostic evaluation and immunotherapy response prediction, current TLS detection and assessment methodologies, as well as potential therapeutic strategies targeting TLS. We employed a systematic literature review methodology. Studies have confirmed that mature, intra-tumoral TLS are significantly correlated with improved patient prognosis and higher immunotherapy response rates, acting as the "central core" of tumor immunity by initiating and sustaining adaptive anti-tumor immune responses locally. Despite the promising clinical translation prospects of TLS, standardization of assessment systems, development of non-invasive detection technologies, and clarification of TLS functional heterogeneity across different HNC subtypes remain major challenges in current research. This review synthesizes the latest advances in this field, providing a comprehensive and insightful perspective for understanding the pivotal role of TLS in HNC treatment.

Keywords:  biological characteristics; head and neck cancer; health management; immunotherapy; tertiary lymphoid structures

DOI:  https://doi.org/10.3389/fimmu.2026.1818962
Cancer Res. 2026 May 27.

Spatially Resolved Molecular Subtyping Uncovers Tumor Progression and Immune Evasion Mechanisms in High-Grade Serous Ovarian Cancer.

Yuelei Zhang, Bin Yang, Xin Hou, Wenxuan Ming, Xin Jin, Gang Chen, Dijun Chen, Wenwei Zhang.

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy characterized by profound intratumoral heterogeneity and immune evasion. While previous research has identified four molecular subtypes of HGSOC, defining their spatial distribution across anatomical sites could help identify functional mediators of progression and immune evasion. In this study, we performed single-cell and spatial transcriptomic sequencing on 66 anatomically paired samples across five sites from eight patients and conducted an integrated analysis on the generated datasets. Five distinct gene programs with specific spatial distributions and functional roles were identified: GP1 (differentiated-invasive), GP2 (differentiated-proliferative), GP3 (immunoreactive), GP4 (mesenchymal), and GP5 (proliferative). Interestingly, molecular subtypes exhibited dynamic spatial transitions that promote HGSOC progression. The differentiated-proliferative subtype dominated tumor cores while the differentiated-invasive subtype localized to the invasive front driven by SDC4-expressing epithelial cells (c40) that were functionally validated to promote migration/invasion. Concurrently, immune evasion operated through distinct mechanisms. Differentiated-invasive and immunoreactive subtypes co-localization established immunosuppression via the TNFα-SAA1/2-APOE signaling axis that recruits immunosuppressive myeloid cells across primary and metastatic sites, while fibroblast-derived collagen barriers were constructed at the interfaces between mesenchymal and immunoreactive subtypes in omental metastases along with dysregulated chemokines to exclude immune infiltration. This spatially resolved atlas directly links subtype spatial transitions to tumor progression and subtype co-localization to immune evasion, providing a mechanistic framework for targeting spatially organized tumor-immune interactions in HGSOC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4749
Biomark Res. 2026 May 27.

The formation and function of tertiary lymphoid structures.

Chengzhang Zhang, Peng Lv, Yaxin Hou, Zhipeng Yao, Shuping Jiang, Ke Chen, Zheng Liu, Lilong Liu.

  Tertiary lymphoid structures (TLSs) are immune cell aggregates that emerge in nonlymphoid tissues during various disease states, including chronic inflammation, autoimmunity, and cancer. TLSs are structurally and functionally analogous to secondary lymphoid organs, and exhibit a maturation continuum (progressing from initial aggregation to mature structures with germinal centers). TLS formation is synergistically regulated by local chemokine networks (e.g. CXCL13, CCL19, and CCL21), lymphotoxin signaling axes, stromal cells, metabolic reprogramming, and the microbiome. This review comprehensively elucidates the biological foundations of TLSs, including their cellular composition, spatial architecture, and developmental dynamics of maturation. We explore the crucial roles of TLSs as favorable prognostic factors and predictors of the immunotherapy response in various solid tumors, including melanoma, breast cancer, lung cancer, hepatocellular carcinoma, and colorectal cancer. Additionally, we analyze their "pathogenic" role in causing tissue damage and disease progression in autoimmune disorders such as rheumatoid arthritis and Sjögren's syndrome, as well as chronic inflammatory diseases such as COPD, IgA nephropathy, and atherosclerosis. In addition, we thoroughly examine TLS research methodologies, covering a wide range of approaches from conventional hematoxylin and eosin (H&E) and immunohistochemical staining to advanced multiplex fluorescence staining, imaging mass spectrometry, and spatial transcriptomic techniques. We summarize multiple gene expression signatures (e.g. the 12-chemokine signature and TLS score) for TLS identification and quantification. Finally, we highlight multiple strategies for artificially inducing TLS formation, including cytokine delivery, immunotherapy, engineered scaffolds, microbiome modulation, and organoid technologies, designed to enhance antitumor immunity or reverse immunopathology. This review provides a comprehensive framework for understanding the complex functions of TLSs in human disease and explores their clinical translation potential as biomarkers and therapeutic targets.

Keywords:  Autoimmunity; Chronic inflammation; Gene expression signatures; Immune checkpoint inhibitors (ICIs); Metabolic reprogramming; Microbiota; TLS induction strategies; Tertiary lymphoid structures; Tumor immunity

DOI:  https://doi.org/10.1186/s40364-026-00939-7
JAMA. 2026 May 28.

Head and Neck Cancer.

Kristin Walter.

DOI: https://doi.org/10.1001/jama.2026.4962
Gynecol Oncol. 2026 May 29. pii: S0090-8258(26)01985-2. [Epub ahead of print]

Four-year survival outcomes with dostarlimab plus chemotherapy in mismatch repair deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer in the RUBY trial.

Matthew A Powell, Henrik Roed, Lyndsay J Willmott, David Cibula, Destin Black, Giorgio Valabrega, Sudarshan Sharma, Stefan Kommoss, Lisa M Landrum, Ingrid Boere, Cara Mathews, Vladyslav Sukhin, Michael A Gold, Caroline Lundgren, Sarah E Gill, Lucy Gilbert, Ilana Cass, Mitchell I Edelson, Joseph Buscema, Nicole S Nevadunsky, Kari Ring, Bhavana Pothuri, Helen D Eshed, Carolyn McCourt, Robert L Coleman, Matthew Grimshaw, Laura Austin, Magdalena Zajac, Brian Slomovitz, Trine Nøttrup.

   OBJECTIVE: Dostarlimab+carboplatin-paclitaxel (CP) demonstrated significant improvement in progression-free survival (PFS) and clinically meaningful improvement in overall survival (OS) vs CP alone among patients with dMMR/MSI-H primary advanced/recurrent endometrial cancer (EC) in Part 1 of the randomized phase 3 RUBY trial (NCT03981796). We report updated efficacy and safety data with approximately 4 years of follow-up.
METHODS: Patients were randomized 1:1 to receive dostarlimab+CP or placebo+CP followed by dostarlimab or placebo up to 3 years or until disease progression. Descriptive analyses of OS and PFS were conducted in the dMMR/MSI-H population (median follow-up, 55.6 months). Post hoc conditional survival analyses and a mixture cure model (MCM) fitted to PFS data to estimate the proportion of patients who had curative potential are presented to provide prognostic insights into long-term survival.
RESULTS: Dostarlimab+CP demonstrated sustained OS and PFS benefits. Median PFS and OS were not reached with a 66% reduction in risk of death vs placebo+CP. PFS curve plateauing (only 4 progression events with additional 2.5 years follow-up since the previous PFS analysis at interim analysis 1) demonstrated durable disease control. Patients alive at the 1- and 2-year landmarks had >80% probability of remaining alive an additional 3 and 2 years, respectively. At 4 years, the MCM analysis estimated a cure rate with dostarlimab of 54% (95% CI 35%-72%). No new safety signals were observed.
CONCLUSIONS: At 4 years, RUBY demonstrated sustained remission and long-term survival benefit, suggesting the potential for curative intent with dostarlimab+CP in patients with dMMR/MSI-H primary advanced or recurrent EC.

Keywords:  Cure model; Dostarlimab; Dostarlimab plus chemotherapy; Mixture cure model; dMMR/MSI-H EC

DOI:  https://doi.org/10.1016/j.ygyno.2026.05.008
Nat Rev Drug Discov. 2026 May 28.

Targeting claudins in cancer.

Yuki Niwa, Shunsuke Matsushita, Izuma Nakayama, Masuo Kondoh.

Epithelial-derived malignancies account for the majority of human tumours and present considerable treatment challenges owing to their heterogeneity, metastatic potential and resistance to therapy. The claudin family of tetra-transmembrane proteins was identified approximately 28 years ago as containing key regulators of epithelial function. These proteins are integral components of tight junctions, which control barrier integrity, selective channel permeability and cellular organization in epithelial tissues. Subsequent murine studies revealed that claudins also have tissue-specific physiological roles, whereas clinical studies demonstrated that their expression is frequently dysregulated in various cancers, highlighting their potential as therapeutic targets. In the past few decades, increasing efforts to exploit claudins in cancer therapy have led to the development of targeted molecules, including zolbetuximab, a first-in-class CLDN-18.2-targeted antibody for the treatment of gastric cancer, which has been recently approved by the United States Food and Drug Administration. This milestone emphasizes the therapeutic potential of targeting this protein family and its possible role in expanding treatment options for cancer. In this review, we discuss the evolving landscape of claudin-targeting therapeutics, examining key advances, emerging challenges and future prospects.

DOI: https://doi.org/10.1038/s41573-026-01450-2