bims-tumhet 2026-06-21 papers

Br J Cancer. 2026 Jun 13.

Can ovarian cancer screening work? A secondary analysis of the UK collaborative trial of ovarian cancer screening.

Jane M Lange, Ishfaq Ahmad, Isabel J Dengos, Andy Ryan, Sophia Apostolidou, Aleksandra Gentry-Maharaj, Shannon Holloway, Marc D Ryser, Usha Menon, Ruth Etzioni.

BACKGROUND: The UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS; 2001-2020) showed no reduction in disease mortality in its primary intervention arm using multimodal screening (MMS) with longitudinal Cancer Antigen 125 (CA125) and transvaginal ultrasound. Whether this null result reflects the stop-screen design, screening performance, or ovarian cancer natural history remains unclear.
METHODS: Using individual-level screening and diagnosis data from the MMS arm, we estimated ovarian cancer natural history, focusing on high-grade serous ovarian cancer (HGSC), the most common and lethal subtype. We then simulated trial outcomes under (1) continued screening beyond the trial screening interval and (2) high sensitivity for early-stage detection over an extended time period.
RESULTS: The estimated window for detecting early-stage HGSC under MMS was <6 months. Continued screening yielded at most a 15% relative mortality reduction. Achieving a ≥20% mortality reduction required extending the detectable early-stage window to 1 year and attaining ≥70% sensitivity during this period.
CONCLUSION: Current screening modalities offer a very limited opportunity to intercept HGSC at an early stage. Clinically effective ovarian cancer screening will require first- and second-line tests capable of detecting HGSC substantially earlier in its natural history.

DOI: https://doi.org/10.1038/s41416-026-03490-2

J Hematol Oncol. 2026 Jun 17.

Cancer-associated fibroblasts and tertiary lymphoid structure orchestrate the spatial architecture of tumor immunity.

Haijia Tang, Youyang Shi, Qintao Ge, Rui Wang, Jianfeng Yang, Yao Zhu, Sheng Liu, Wenhao Xu.

Tumor immunity is shaped not only by the cellular composition of the tumor microenvironment (TME), but also by how stromal and immune elements are spatially organized within it. Among these regulators, cancer-associated fibroblasts (CAFs) and tertiary lymphoid structures (TLS) have emerged as two major determinants of the spatial niche of anti-tumor immunity. CAFs comprise heterogeneous and plastic stromal populations that can remodel the extracellular matrix, restrict lymphocyte infiltration, sustain chronic inflammation, and promote therapeutic resistance, while selected subsets may also support antigen presentation and lymphoid organization. In contrast, TLS function as ectopic immune hubs that coordinate local T- and B-cell priming, clonal expansion, and B-cell maturation, and are increasingly associated with favorable prognosis and improved responses to immune checkpoint blockade. In this review, we synthesize recent advances from single-cell and spatial multi-omics studies to examine how CAF states and TLS maturation programs arise, interact, and remodel the immune landscape across tumor types. We propose that the balance between CAF-driven stromal restriction and TLS-associated immune organization is a central determinant of immune exclusion versus immune activation. We discuss how this spatial framework may refine tumor classification, improve patient stratification, and guide therapeutic strategies aimed at stromal reprogramming, TLS induction or maturation, and rational combination immunotherapy, while highlighting innate immune-stromal circuits, including IL-33-activated ILC2s, NCR⁺ ILC3s, LTi-like programs, and myeloid organizer cells, as upstream regulators of TLS neogenesis. By integrating CAF biology, TLS dynamics, and spatial context, this review provides a conceptual framework for understanding and targeting the stromal architecture of tumor immunity.

Keywords: Cancer-associated fibroblasts (CAF); Immunotherapy; Spatial niche; Tertiary lymphoid structures (TLS); Tumor microenvironment (TME)

DOI: https://doi.org/10.1186/s13045-026-01814-6

Front Immunol. 2026 ;17 1827875

Tertiary lymphoid structures in breast cancer: formation, immune functions and clinical implications.

Wenting Dong, Shichao Ai, Xiaofei Shen, Yongzhong Yao.

Tertiary lymphoid structures (TLS) are ectopic lymphoid aggregates that arise in non-lymphoid tissues under chronic inflammatory conditions and during tumor development. Although TLS have often been associated with a favorable prognosis and enhanced therapeutic responsiveness, their biological and clinical significance in breast cancer is highly heterogeneous and cannot be adequately captured by a simple TLS-positive versus TLS-negative classification. In this review, we summarize the structural organization and developmental stages of TLS, with an emphasis on the functional relevance of maturation, including germinal center formation. We further discuss current concepts regarding the mechanisms driving TLS initiation and maturation, including stromal activation, chemokine-guided immune cell recruitment, and high endothelial venule-mediated lymphocyte trafficking. In addition, we examine the major dimensions of TLS heterogeneity in breast cancer, including differences in maturity, spatial location, molecular subtype, and immune cellular composition, and discuss how these variables shape antitumor, immunoregulatory, and context-dependent TLS functions. We also evaluate the current approaches for TLS identification and classification, highlighting the strengths and limitations of histopathology, immunophenotyping, multiplex imaging, and transcriptomic inference. Finally, we discuss the prognostic and predictive relevance of TLS in breast cancer, the barriers limiting its clinical translation, and key priorities for future research. Overall, TLS status represents a promising but context-dependent biomarker and potential therapeutic intermediate whose interpretation requires standardized classification and a deeper mechanistic understanding.

Keywords: breast cancer; immune checkpoint blockade; immunotherapy; prognostic biomarkers; tertiary lymphoid structures; tumor immunity; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2026.1827875

Nat Cancer. 2026 Jun 18.

The future of tertiary lymphoid structures in cancer immunotherapy as biomarkers and therapeutic targets.

Hye Mi Kim, Tejashree Joglekar, Tina Cascone, Tullia C Bruno.

DOI: https://doi.org/10.1038/s43018-026-01188-1

Front Oncol. 2026 ;16 1853078

The TRUST trial in ovarian cancer: a missed opportunity or a turning point? The position of the Italian MITO group.

Martina Arcieri, Sandro Pignata, Domenica Lorusso, Anna Fagotti, Vito Chiantera, Antonino Ditto, Giorgio Valabrega, Claudia Marchetti, Claudio Zamagni, Valentina Tuninetti, Alberto Farolfi, Stefano Restaino, Giuseppe Vizzielli.

Keywords: Cytoreduction; neoadjuvant chemotherapy; ovarian cancer; randomized clinical trial; surgery

DOI: https://doi.org/10.3389/fonc.2026.1853078

Int J Clin Oncol. 2026 Jun 13.

Mirvetuximab soravtansine in platinum-resistant ovarian cancer: from biological rationale to clinical impact and future directions.

Seiji Mabuchi, Ai Kusakabe, Tomoyuki Sasano.

Platinum-resistant ovarian cancer (PROC) remains a major clinical challenge due to limited therapeutic options and poor prognosis. Conventional treatments provide only modest benefits, and immune checkpoint inhibitors have shown limited efficacy in unselected populations, underscoring the need for biomarker-driven strategies. Mirvetuximab soravtansine (MIRV) is a first-in-class antibody-drug conjugate targeting folate receptor alpha (FRα), which is highly expressed in a substantial proportion of epithelial ovarian cancers. By combining selective tumor targeting with intracellular delivery of the cytotoxic payload DM4, MIRV achieves potent antitumor activity with a manageable safety profile and evidence of a clinically relevant bystander effect. Clinical trials including SORAYA and MIRASOL demonstrated that MIRV significantly improved response rates, progression-free survival, and overall survival in patients with FRα-high PROC, thereby establishing MIRV as a clinically meaningful treatment option. Ongoing research is evaluating MIRV by using combination regimens, earlier treatment lines, and maintenance strategies. Despite these advances, challenges remain, including resistance mechanisms, optimization of biomarker assessments, and cost considerations. Future efforts should focus on refined patient selection, rational combination strategies, and next-generation antibody-drug conjugates, which are expected to further expand the clinical utility of FRα-targeted therapy.

Keywords: Antibody–drug conjugate; Biomarker-driven therapy; Folate receptor alpha; Mirvetuximab soravtansine; Platinum-resistant ovarian cancer

DOI: https://doi.org/10.1007/s10147-026-03090-3