bims-tumhet 2026-07-19 papers

Issue of 2026–07–19
four papers selected by
Sergio Marchini, Humanitas Research

Mol Oncol. 2026 Jul 12.

Translating whole-genome doubling into precision medicine in cancer.

Sejung Lee, Junghyeok Lim, Jinhyuk Bhin.

Whole-genome doubling (WGD) occurs in approximately 30-40% of human cancers, representing a transformative evolutionary event that fundamentally reshapes tumor biology. WGD triggers chromosomal instability (CIN) and somatic copy-number alterations (SCNAs), which accelerate tumor evolution and underlie aggressive clinical behavior. Paradoxically, the same cellular stresses that drive tumor progression also force WGD-positive cells into a heightened dependence on specific survival mechanisms, meaning that poor prognosis and therapeutic vulnerability arise from the same underlying phenomenon. Despite the widespread occurrence and clinical impact of WGD, translating its biology into actionable therapeutic strategies remains limited due to the lack of prospective evidence and integrated biomarker frameworks. This review provides a comprehensive overview of WGD biology, from mechanisms to clinical applications, examining how WGD arises and drives tumor evolution, its prevalence and prognostic impact across cancer types, and the emerging therapeutic vulnerabilities that WGD-positive tumors expose.

Keywords: cGAS‐STING; chromosomal instability; polyploidy; precision oncology; tumor evolution; whole‐genome doubling

DOI: https://doi.org/10.1002/1878-0261.70302

Front Immunol. 2026 ;17 1882195

Tertiary lymphoid structures as biomarkers and therapeutic targets in neoadjuvant cancer immunotherapy.

Tong Wang, Wenlong Xu, Xiaofeng Wu.

Neoadjuvant immunotherapy is reshaping the treatment of resectable solid tumors, but biomarkers that reflect spatially organized antitumor immunity remain limited. Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that support local antigen presentation, lymphocyte recruitment, T-B cell interaction, germinal center reactions and humoral immunity. Increasing evidence suggests that TLS density, maturation, localization and cellular composition are associated with immune checkpoint blockade response, pathological regression and prognosis. Beyond their biomarker value, TLS may represent modifiable immune niches that can be induced or remodeled by checkpoint blockade, chemotherapy, radiotherapy, vaccines and stromal-vascular strategies. This mini-review discusses the biological basis, biomarker potential, therapeutic targeting and clinical translation of TLS in neoadjuvant cancer immunotherapy, highlighting key challenges and future TLS-guided trial designs.

Keywords: immune checkpoint blockade; neoadjuvant immunotherapy; predictive biomarker; tertiary lymphoid structures; tumor microenvironment remodeling

DOI: https://doi.org/10.3389/fimmu.2026.1882195

Clin Cancer Res. 2026 Jul 13.

Role of ctDNA Tumor Fraction in Selecting Immunotherapy Based Regimens in Advanced Non-small Cell Lung Cancer.

BACKGROUND: Immune checkpoint blockers (ICBs) have transformed advanced non-small cell lung cancer (aNSCLC) treatment, but identifying patients who benefit from adding chemotherapy remains challenging, especially in PD-L1 ≥ 50%. PD-L1 is an imperfect biomarker, highlighting the need for better selection tools.
METHODS: Liquid biopsy (LBx) assessment was performed using hybrid capture-based next-generation sequencing of plasma cell-free DNA. LBx data, molecular profile, and clinico-pathological data were collected. The predictive and prognostic values of tumor fraction (TF) were assessed using a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB). An independent cohort with aNSCLC from Gustave Roussy was used to validate the findings and to study the correlation of ctDNA tumor fraction and total metabolic tumor volume (tMTV) and its molecular correlates.
RESULTS: In the CGDB Database (n=965), elevated ctDNA TF was prognostic for worse outcomes on ICBs and, when ≥5%, predictive of benefit from ICB+chemotherapy (HR for real-world progression-free survival 0.58 [0.41-0.82], p=0.002). The 5% cutoff for TF was validated in an independent cohort from Gustave Roussy. In 283 patients with paired PET scans, ctDNA TF correlated with metabolic tumor volume (rho=0.46, p<0.001) and was influenced by TP53/RB1 mutations.
CONCLUSIONS: ctDNA TF integrates disease burden and biology. Patients with high ctDNA TF derive greater benefit from chemo-immunotherapy, supporting its use as a biomarker to guide treatment intensification.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-3917

Science. 2026 Jul 16. 393(6808): eady1678

Dendritic cells control tertiary lymphoid structure development and maintenance in cancer.

Raphaël Mattiuz, Jesse Boumelha, Emmanouil Aerakis, Jessica Le Berichel, Pauline Hamon, Laszlo Halasz, Abishek Vaidya, Brian Y Soong, Emir Radkevich, Hye Mi Kim, Matthew D Park, Romain Donne, Leanna Troncoso, Rachel A Kaplan, Clotilde Hennequin, Isaias Hernández-Verdin, Lucía López, Frederika Rentzeperis, Darwin D'Souza, Medard Ernest Kaiza, Ian P MacFawn, Meriem Belabed, Guillaume Mestrallet, Etienne Humblin, Raphaël Merand, Samarth Hegde, Jean-Christophe Lone, Giorgio Ioannou, Sinem Ozbey, Igor Figueiredo, Alexander Tepper, Hajer Merarda, Nadine Serhan, Maximilian M Schaefer, Jinping An, Ray A Ohara, Erika Nemeth, Simon Goldstein, Amanda M Reid, Moataz Noureddine, Alexandra Tabachnikova, Giulia Maria Piperno, Maria Tsoumakidou, Jalal Ahmed, Alexandros D Polydorides, Nina Bhardwaj, Amaia Lujambio, Zhihong Chen, Edgar Gonzalez Kozlova, Seunghee Kim-Schulze, Joshua D Brody, Michael Schotsaert, Christine Moussion, Sacha Gnjatic, Vladimir Roudko, Florent Ginhoux, Kenneth M Murphy, Catherine Sautès-Fridman, Wolf Herman Fridman, Brian D Brown, Thomas U Marron, Federica Benvenuti, Jason G Cyster, Hélène Salmon, Tullia C Bruno, Nikhil S Joshi, Alice O Kamphorst, Miriam Merad.

Tertiary lymphoid structures (TLSs) are associated with immunotherapy response, yet the mechanisms controlling their formation and maintenance remain unclear. Using spatial transcriptomics and multiplex imaging across human tumors, we found that CCR7+ mature dendritic cells (DCs) accumulate in TLSs. In a mouse non-small cell lung cancer model that forms mature TLSs, we show that early TLS development requires interferon-γ (IFN-γ)-driven type 1 conventional dendritic cell (cDC1) maturation, migration to tumor-draining lymph nodes (tdLNs), and T cell recruitment. As tumors progress, TLSs persist independently of tdLN T cell egress, coinciding with cDC1 accumulation within intratumoral CCL19 stromal hubs. There, cDC1-major histocompatibility complex class 1 (MHC-I) and -MHC-II concomitant antigen presentation, along with CD40 signaling, sustain TLS, T follicular helper (TFH) cell pool, germinal centers, and tumor-specific immunoglobulin G (IgG). These findings highlight local mature cDC1s as key TLS orchestrators and potential targets to enhance antitumor TLS function.

DOI: https://doi.org/10.1126/science.ady1678