Malignant tumors have long been typified as “immune cold” due to their ability to evade immune detection and suppress immune activity, rendering many conventional treatments ineffective. This immune evasion has posed significant challenges in oncology, as patients with immune-cold tumors often experience poor responses to chemotherapy and immunotherapy, culminating in dire prognoses. The Johns Hopkins team’s novel approach aims to reverse this phenomenon by transforming these tumors into “immune hot” environments that actively recruit and stimulate immune cells to attack cancer.

Central to this transformative approach are tertiary lymphoid structures (TLSs), which are lymph node-like aggregates that naturally form in sites afflicted by chronic inflammation, including certain tumors responsive to the immune system. TLSs serve as immunological hubs within tumors and have been strongly correlated with improved patient prognoses and responsiveness to therapy. Understanding the factors that foster TLS formation in tumors has been a pivotal goal in harnessing their anti-cancer potential.

Leveraging previous insights in breast cancer immunology, the researchers hypothesized that enhancing the local tumor milieu with specific immune-activating signals could fortify TLS development and functionality. They meticulously studied the complex cellular and molecular landscape of TLS-rich tumors to identify the critical stimuli driving their formation and activity. This reverse-engineering approach provided a blueprint for inducing TLS presence in otherwise TLS-deficient tumors.

The experimental intervention centered on simultaneously activating two key immune signaling pathways: the stimulator of interferon genes (STING) and the lymphotoxin-β receptor (LTβR). STING is a cytosolic DNA sensor that initiates robust innate immune responses, including the production of type I interferons and other inflammatory cytokines, thereby shaping adaptive immunity. LTβR signaling is essential for lymphorganogenesis and maintaining the structural integrity of lymphoid tissues. By delivering agonists that engage both STING and LTβR, the researchers engineered a highly stimulatory tumor environment conducive to immune cell recruitment and activation.

This dual activation regime precipitated a swift and powerful infiltration of cytotoxic CD8⁺ T cells into the tumor microenvironment, directly contributing to pronounced tumor growth inhibition. Notably, the treatment induced the formation of high endothelial venules (HEVs)—specialized blood vessels that function as selective gateways permitting lymphocyte extravasation from the bloodstream into the tumor stroma. The emergence of HEVs effectively opened the floodgates, enabling massive recruitment of both B cells and T cells to forge new TLS in situ.

Within these newly formed TLS, B lymphocytes exhibited hallmark germinal center reactions, a sophisticated immune process whereby B cells proliferate, undergo somatic hypermutation, and mature into plasma cells capable of producing high-affinity, tumor-specific antibodies. These plasma cells not only sustained local antibody production but also migrated to the bone marrow to establish a reservoir of long-lived memory cells. The presence of tumor-specific IgG antibodies and persistent plasma cells underscores the generation of durable systemic immunity capable of long-term tumor surveillance and relapse prevention.

Concurrently, the immunotherapy elevated populations of helper CD4⁺ T cells and memory CD8⁺ T cells, thereby orchestrating a balanced enhancement of humoral and cellular immunity. This comprehensive immune orchestration ensures that both antibody-mediated mechanisms and direct cytotoxic effects contribute synergistically to tumor eradication. Modulating immune signaling balance within the tumor bed appears critical for sustaining sustained anti-tumor activity.

These findings illuminate a mechanistically rich paradigm in which early, dual-pathway immune activation not only exerts immediate cytotoxic effects on tumor cells but also fosters the maturation and persistence of TLS that amplify and sustain anti-cancer immune responses over time. TLS maturation thereby operates as an immunological amplifier system, extending the reach and durability of immune-mediated tumor control well beyond the initial treatment window.

Dr. Masanobu Komatsu, principal investigator and senior scientist at the Johns Hopkins All Children’s Cancer & Blood Disorders Institute, emphasizes the transformative potential of this approach. “By constructing the appropriate immune architecture within tumors, we can potentiate both T cell and B cell defenses against cancer progression, relapse, and metastasis,” he states. This dual-pronged, immune-structural remodeling strategy promises to overcome the entrenched immunosuppressive barriers characteristic of many aggressive cancers.

Because the abundance of TLS has been positively associated with outcomes across diverse tumor types, this dual activation of STING and LTβR may offer a broadly applicable therapeutic avenue. It holds potential to substantially boost the efficacy of existing modalities, including checkpoint inhibitor immunotherapies, which often falter in “immune cold” cancers, as well as traditional chemotherapeutic regimens. Enhancing the tumor’s inherent immune competence could therefore represent a universal adjunct to improve cancer treatment paradigms.

Ongoing research efforts by Komatsu’s team are delving deeper into the complex molecular mechanisms underlying TLS induction and function following STING and LTβR stimulation. Furthermore, preparations are underway to translate these preclinical findings into clinical trials involving both adult and pediatric cancer patients. These future studies aim to validate safety, optimize dosing, and determine the most effective combination regimens to integrate TLS induction with current immuno-oncology standards.

Funded principally by NIH/National Cancer Institute grants alongside support from the Department of Defense’s Congressionally Directed Cancer Research Program and the Florida Department of Health Bankhead Coley Cancer Research Program, this research reflects a significant multidisciplinary collaboration. The work’s potential to fundamentally alter cancer immunotherapy highlights the critical role of federally supported science in pushing the boundaries of medical innovation.

As immunotherapy revolutionizes cancer care, the ability to deliberately engineer tumor microenvironments to foster TLS formation marks a bold and exciting frontier. This therapeutic blueprint exemplifies how reprogramming immune system architecture within tumors can unmask new vulnerabilities in cancer. Ultimately, such innovations stand to shift the paradigm from merely treating tumors to empowering the body’s own immune machinery to deliver durable, systemic tumor control and improve patient survival worldwide.

Subject of Research: Enhancing anti-tumor immunity by inducing tertiary lymphoid structures via dual STING and LTβR activation in immune-cold tumors

Article Title: Therapeutic induction of tertiary lymphoid structures promotes durable anti-cancer immunity in immune-cold tumors

News Publication Date: September 2, 2025

Web References:
https://www.nature.com/articles/s41590-025-02259-8?fromPaywallRec=false#Sec11

References:
Johns Hopkins All Children’s Hospital research publication in Nature Immunology, 2025

Image Credits:
Nature Immunology

Keywords:
Cell lines, Cancer cells

Mesothelioma, particularly diffuse pleural mesothelioma, remains a formidable clinical challenge. This aggressive malignancy, predominantly linked to asbestos exposure, has historically seen sparse improvements in survival outcomes. Immunotherapy, especially checkpoint inhibitors targeting PD-1 and CTLA-4 pathways, has revolutionized care for patients with inoperable disease, yet its utility in operable cases remained largely uncharted. The current study closes this gap by investigating neoadjuvant nivolumab, alone or combined with ipilimumab, followed by surgery and adjuvant nivolumab, demonstrating both safety and encouraging survival benefits.

The clinical trial enrolled patients with resectable mesothelioma, with over 80% successfully undergoing surgery within a predetermined window after receiving preoperative immunotherapy. Remarkably, those treated with the dual checkpoint blockade—nivolumab and ipilimumab—achieved a median overall survival of 28.6 months, significantly exceeding the historical average survival of 18 months for mesothelioma. Approximately 36% of these patients remained alive without recurrence at follow-up, underscoring the regimen’s potential to induce durable responses.

What sets this research apart is the comprehensive integration of tumor-informed, ultra-sensitive whole genome sequencing liquid biopsies to monitor circulating tumor DNA (ctDNA). This innovative approach addresses a critical limitation in mesothelioma management: the difficulty of tracking minimal residual disease using conventional imaging or mutation-based liquid biopsies due to the tumor’s low mutational burden. By sequencing the entire genome of tumor-derived DNA fragments in the bloodstream, clinicians can detect microscopic cancer persistence with unprecedented sensitivity.

This liquid biopsy strategy enabled the research team to uncover clinically meaningful insights unattainable through imaging alone. Patients exhibiting undetectable ctDNA levels after neoadjuvant therapy or a reduction of 95% or more during treatment experienced significantly better event-free and overall survival. Conversely, persistent ctDNA signaled impending disease progression, even when radiographic studies remained stable, facilitating earlier intervention decisions.

According to Dr. Valsamo “Elsa” Anagnostou, the study’s senior author and Alex Grass Professor of Oncology, the feasibility and potential efficacy of perioperative combination immune checkpoint blockade mirror successes seen in lung cancer. This parallel not only validates the approach but also opens a new therapeutic avenue for mesothelioma patients who have limited options. The incorporation of ultra-sensitive ctDNA monitoring further adds a layer of precision medicine that could transform individualized treatment decisions.

Technical challenges, such as the low somatic mutation count of mesothelioma tumors, historically hampered mutation-based liquid biopsy approaches. This study surmounts those obstacles by employing genome-wide sequencing that captures ctDNA irrespective of specific mutations, thereby enabling robust detection and dynamic treatment monitoring. Dr. Paul Lee, co-first author, highlighted that this advancement paves the way for clinically actionable, minimally invasive biomarkers that can guide real-time management of residual disease and relapse.

The trial exemplifies multidisciplinary collaboration among numerous academic cancer centers and leverages pharmaceutical partnership, with Bristol Myers Squibb sponsoring the study. Funding from a diverse array of agencies—including the Department of Defense, NIH, FDA, and multiple cancer research foundations—fueled the ambitious scope, ensuring rigorous study design and comprehensive molecular analyses.

In addition to survival metrics, the study illuminates the biologic underpinnings of treatment response and resistance. Monitoring ctDNA dynamics enabled the discernment of patients most likely to benefit from immunotherapy versus those who may require intensified or alternative interventions. This tailored approach holds promise for optimizing therapeutic efficacy while mitigating unnecessary toxicity.

While these findings mark a significant stride in mesothelioma treatment, the authors caution that further investigation is necessary to validate ctDNA as a surrogate marker and refine perioperative immunotherapy protocols. Nonetheless, the demonstrated safety and encouraging survival outcomes provide a compelling rationale for expanded clinical trials and potential integration into standard care.

The confluence of advanced immunotherapy and sensitive genomic monitoring heralds a new era of precision oncology in mesothelioma. This paradigm shift underscores the imperative of combining systemic therapies with molecular diagnostics to outsmart one of the most lethal thoracic malignancies.

As this work progresses, it may catalyze broader applications of perioperative immunotherapy and liquid biopsy surveillance in other low-mutation cancers, broadening the frontier of personalized cancer treatment. For a disease long devoid of substantial improvements, these findings offer renewed hope and a clear path forward for patients and clinicians alike.

Subject of Research: Combination perioperative immunotherapy and ctDNA monitoring in operable mesothelioma

Article Title: Perioperative Combination Immune Checkpoint Blockade and Ultra-Sensitive ctDNA Analysis in Resectable Mesothelioma

News Publication Date: September 8, 2025

Web References:

• Johns Hopkins Kimmel Cancer Center: https://www.hopkinsmedicine.org/kimmel-cancer-center
• Bloomberg-Kimmel Institute for Cancer Immunotherapy: https://www.hopkinsmedicine.org/kimmel-cancer-center/bloomberg-kimmel-institute-for-cancer-immunotherapy
• Original Study in Nature Medicine: https://www.nature.com/articles/s41591-025-03958-3

References: Study presented at the 2025 World Conference on Lung Cancer; multiple grants and institutional supports as detailed in the original publication.

Keywords: Cancer cells, Cancer genomics, Mesothelioma, Immunotherapy, Immune checkpoint blockade, Neoadjuvant therapy, Circulating tumor DNA, Liquid biopsy, ctDNA, Precision oncology, Ultra-sensitive sequencing, Perioperative treatment

Historically, the detection of prostate cancer has heavily depended on blood tests measuring PSA, a protein produced by both cancerous and noncancerous prostate tissues. Although PSA testing has been an essential tool in screening, its specificity is limited. Elevated PSA levels above 4.0 nanograms per milliliter often prompt urologists to recommend prostate biopsies, which involve extracting multiple tissue samples via needles. However, these biopsies can be negative or result in overtreatment of low-grade prostate cancers unlikely to progress aggressively. This gap in diagnostic precision has driven the need for more accurate, minimally invasive methods.

The team spearheaded by Dr. Ranjan Perera, director of the Center for RNA Biology at Johns Hopkins All Children’s Hospital, employed advanced molecular profiling techniques to analyze urine samples from prostate cancer patients before and after prostatectomy, as well as from healthy individuals. By meticulously isolating prostate cells shed in urine and conducting RNA sequencing alongside real-time quantitative polymerase chain reaction (qPCR), researchers narrowed down 815 prostate-specific genes to a critical trio: TTC3, H4C5, and EPCAM. These markers were robustly linked to the presence of prostate cancer, showing significant expression in pre-surgery urine samples and near absence following surgical removal of the prostate.

TTC3, or tetratricopeptide repeat domain 3, is particularly notable for its role in asymmetric cell division in cancerous cells, a process vital to tumor heterogeneity and progression. H4C5 refers to an H4 clustered histone variant, a protein influential in chromatin remodeling, which impacts gene expression regulation and genome stability within malignant cells. EPCAM, the epithelial cell adhesion molecule, is a surface glycoprotein commonly overexpressed in epithelial-derived cancers. The synergistic detection of these three biomarkers in urine offers a molecular fingerprint that is both highly sensitive and specific to prostate malignancies.

In comprehensive validation studies, the three-marker panel demonstrated an impressive area under the curve (AUC) of 0.92, indicating near-perfect diagnostic performance. The test accurately identified prostate cancer in 91% of cases and effectively ruled out non-cancerous individuals 84% of the time. Remarkably, it also distinguished prostate cancer patients from those with benign prostatic hyperplasia (BPH), a benign enlargement of the prostate that often confounds clinical diagnoses. This specificity extends even to patients whose PSA levels remain within normal ranges, addressing a critical diagnostic blind spot where current PSA tests falter.

The researchers did not stop at typical PSA-positive cases but intentionally investigated the panel’s effectiveness in PSA-negative prostate cancers. Even within this challenging subset, the test retained high diagnostic accuracy, correctly identifying malignancies in 78.6% of cases during development and 85.7% during validation. Such sensitivity could transform early detection protocols for men who otherwise might be overlooked by PSA screening. Furthermore, this assay showed the ability to differentiate prostate cancer from prostatitis, an inflammatory prostate disease that can also obscure clinical assessments.

The methodology entailed extensive sample collection from multiple centers, capturing a diverse cross-section of patients and controls. In total, the study evaluated over 1,300 urine specimens across both development and validation phases, ensuring statistical robustness. The high-throughput analyses coupled with immunohistochemical studies on tissue biopsies correlated biomarker expression in urine with that observed directly in malignant prostate tissues. This multi-platform validation confirms that these biomarkers derive specifically from prostate cancer cells, reinforcing the biological relevance of the test.

Current prostate cancer diagnostic standards are burdened by the limitations of PSA screening – namely its lack of specificity and the invasive nature of follow-up biopsies. As Dr. Perera emphasizes, these biopsies carry risks such as infection and bleeding, and negative results occur frequently, leading to patient anxiety and increased healthcare costs. By introducing a sensitive, urine-based assay, patients could potentially avoid these invasive procedures altogether unless clearly indicated, optimizing both patient well-being and resource allocation.

Co-author Dr. Christian Pavlovich, a distinguished professor of Urologic Oncology, highlights the clinical practicality of urine as a diagnostic medium. Given that urine collection is noninvasive, inexpensive, and easy to implement in outpatient settings, the adoption of such a test could be swift and widespread, enhancing prostate cancer screening while reducing dependence on blood-based PSA measurements. The test’s ability to act as an adjunct or standalone diagnostic tool heralds a new era in precision urology.

Looking ahead, investigators are contemplating integrating the three-biomarker panel with PSA testing to create a “super PSA” assay, combining the strengths of both approaches to maximize diagnostic accuracy. Clinical trials at independent institutions are planned to further validate the assay’s performance, with the ultimate goal of transitioning this discovery from research laboratories into clinical practice. Efforts are also underway to patent the technology and explore commercial development opportunities through technology transfer and startup formation.

The research, supported by several funding agencies including the National Institutes of Health, the Bankhead-Coley Cancer Research Program, and the International Prostate Cancer Foundation, signifies a major leap forward in biomarkers for urologic oncology. As this panel advances through clinical validation and regulatory review, it promises to redefine prostate cancer diagnosis, improving patient outcomes through earlier intervention and reducing the emotional and physical toll of unnecessary procedures.

In conclusion, this innovative urine test targeting TTC3, H4C5, and EPCAM biomarkers marks a transformative step towards precision medicine in prostate cancer. With its superior sensitivity, specificity, and noninvasive nature, it addresses critical limitations in current screening paradigms and paves the way for personalized diagnostic strategies. This scientific milestone reflects a multidisciplinary triumph, blending molecular biology, clinical oncology, and cutting-edge technology to confront one of the most prevalent malignancies affecting men worldwide.

Subject of Research: Prostate cancer diagnosis using urine biomarkers
Article Title: Novel Urine Biomarker Panel Demonstrates High Accuracy for Noninvasive Prostate Cancer Detection
News Publication Date: September 2, 2025
Web References: Johns Hopkins Kimmel Cancer Center (https://www.hopkinsmedicine.org/kimmel_cancer_center/), Johns Hopkins All Children’s Hospital (https://www.hopkinsmedicine.org/all-childrens-hospital)
References: Published in EBioMedicine on September 2, 2025
Image Credits: Johns Hopkins All Children’s Hospital
Keywords: Prostate cancer, biomarkers, TTC3, H4C5, EPCAM, urine test, noninvasive diagnostics, PSA, biopsy alternative