Researchers from University College London, Oxford, and Leicester have developed a flow-enabled 3D micro-bladder model to better understand recurrent urinary tract infections and evaluate phage therapy effectiveness. This novel platform integrates a fluidic system that mimics urine flow dynamics, providing a more physiologically relevant testing environment than traditional static lab cultures. The study revealed that uropathogenic Escherichia coli, responsible for most UTIs, demonstrates significantly higher infectivity in the flow-augmented model, with bacteria infiltrating the bladder lining and forming persistent reservoirs that likely explain frequent UTI recurrence. When tested in this advanced model, nitrofurantoin, a first-line antibiotic, proved less effective than in standard susceptibility tests, highlighting why current treatments often fail in patients. The research addresses a critical clinical problem: antibiotics frequently fail to completely eliminate UTI infections due to growing antimicrobial resistance. By demonstrating that bacteriophage therapy shows promise in this more realistic tissue model, this work offers a potential alternative treatment strategy for recurrent UTIs and underscores the importance of physiologically accurate testing systems for translating laboratory findings into effective clinical therapies.

In the phase 1b/2 BEGONIA platform trial, the combination of trastuzumab deruxtecan and durvalumab demonstrated remarkable efficacy as a first-line treatment for hormone-receptor-negative, HER2-low metastatic breast cancer. Trastuzumab deruxtecan, developed by Daiichi Sankyo and AstraZeneca, is an antibody-drug conjugate that delivers potent chemotherapy directly to HER2-expressing cells, while durvalumab blocks PD-L1 to enhance immune activation. The combination achieved tumor shrinkage in approximately sixty percent of patients, with many maintaining responses at analysis completion—an unusually durable pattern for this aggressive disease. Hormone-receptor-negative breast cancer, predominantly triple-negative, ranks among the most lethal breast cancer subtypes, affecting younger women disproportionately and progressing rapidly to distant organs. Traditional treatment relies on cytotoxic chemotherapy with platinum salts and taxanes, with limited immunotherapy benefit restricted to PD-L1 high-expressing tumors. The BEGONIA findings, published in Nature Cancer, represent the most mature clinical evidence yet for combining HER2-targeted therapy with immunotherapy in this population, potentially transforming treatment paradigms for patients previously limited to nonselective chemotherapy approaches.

Cancer immunotherapies, including adoptive T-cell therapies and checkpoint inhibitors, have revolutionized treatment for many malignancies, yet only a subset of patients achieve durable responses. The tumor metabolic microenvironment significantly contributes to this therapeutic gap. Tumor cells compete with infiltrating lymphocytes for essential nutrients like glucose and glutamine while accumulating immunosuppressive metabolites including lactate, adenosine, and kynurenine. This metabolic stress drives T-cell mitochondrial dysfunction and exhaustion, compromising treatment efficacy. Metabolomics has emerged as a critical analytical tool bridging these observations with interventions. Advanced techniques including mass spectrometry, spatial metabolic imaging, stable-isotope flux analysis, and single-cell profiling now enable detailed mapping of metabolite gradients and identification of treatment-response biomarkers. Parallel efforts focus on metabolic reprogramming of CAR-T and TCR-T therapies, dietary interventions, and targeting metabolic checkpoints to enhance T-cell function. However, significant challenges remain: metabolomic findings are often correlative rather than causal, spatial resolution within tumors is limited, and translation from preclinical models to patients remains inconsistent. This research initiative seeks mechanistic, translational, and clinical studies advancing causal understanding of cancer metabolomics in T-cell immunotherapy, ultimately improving patient outcomes through validated metabolic biomarkers and novel therapeutic strategies.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized blood cancer treatment with seven FDA-approved options, yet conventional manufacturing remains time-consuming, expensive, and produces variable outcomes. Nyberg and colleagues published a groundbreaking study in Nature (2026) proposing an innovative in vivo approach to circumvent these manufacturing bottlenecks. Rather than extracting and engineering T cells outside the body, their two-vector system delivers CRISPR-Cas9 machinery directly to patients to generate CAR T cells within the body itself. The strategy specifically targets the T-cell receptor alpha constant (TRAC) locus, a T-cell-specific genomic site enabling sustained, physiological CAR expression while minimizing off-target integration risks. The researchers employed optimized adeno-associated viruses (AAVs) and enveloped delivery vehicles (EDVs), including a novel AAV-hT7 capsid with enhanced performance in human serum and T-cell targeting. In humanized mouse models, this approach successfully generated therapeutic CAR T-cell levels and controlled tumor growth. This advancement addresses critical clinical challenges by potentially accelerating treatment timelines, reducing manufacturing complexity and costs, and improving product consistency, thereby democratizing access to CAR T therapy.

Merck and Moderna announced positive Phase 3 results for intismeran autogene, a personalized mRNA cancer vaccine, marking a watershed moment for oncology immunotherapy. The INTerpath-001 trial enrolled 1,137 patients with surgically resected high-risk melanoma (stages IIB-IV) and demonstrated that intismeran combined with Merck's checkpoint inhibitor pembrolizumab (Keytruda) achieved statistically significant improvements in both recurrence-free survival and distant metastasis-free survival compared to pembrolizumab monotherapy. Critically, this represents the first positive Phase 3 readout for any individualized neoantigen mRNA cancer therapy. No new safety signals emerged, with tolerability consistent with previous reports. Unlike conventional treatments, intismeran is personalized; each dose is tailored to the individual patient's tumor mutations. Study principal investigator Georgina Long emphasized the potential to establish a new treatment paradigm in adjuvant melanoma care, while Yale dermatologist Christopher Bunick called it "one of the most monumental advancements" in dermatology. This milestone validates mRNA's transition from experimental promise to clinical proof in cancer treatment, pending regulatory approval.

In a paper published recently in the Proceedings of the National Academy of Sciences (PNAS), a team led by Eugene Shakhnovich, Roy G. Gordon Professor of Chemistry, and Vaibhav Mohanty, an M.D./Ph.D. student at the Harvard Kenneth C. Griffin Graduate School of Arts and Sciences and Harvard-MIT Division of Health Sciences and Technology, describes a way to engineer the evolutionary landscape that viruses experience, pushing them away from dangerous variants and into evolutionary dead ends.

AstraZeneca is advancing cell therapy research to expand treatment possibilities beyond current applications in blood cancers to solid tumors and autoimmune diseases. The company is developing three distinct platforms: autologous therapies that isolate and engineer a patient's own T cells to target disease; allogeneic off-the-shelf therapies created from donor T cells for immediate availability to multiple patients; and in vivo therapies using viral vectors to reprogram T cells directly within the body. These approaches include CAR-T cells engineered to recognize surface proteins on disease cells and TCR-T cells designed to target intracellular cancer-specific mutations. AstraZeneca's strategy focuses on harnessing the immune system's natural defenses by engineering T cells to precisely attack cancer cells and reset immune-mediated disease drivers. By investing in state-of-the-art platforms and building global capabilities, the company aims to democratize cell therapy access worldwide, removing barriers that currently limit patient benefit and unlocking the full curative potential of this innovative modality across multiple therapeutic areas.

Cancer immunotherapy has revolutionized oncology by shifting treatment focus from targeting tumor cells to modulating patient immune responses. Immune checkpoint inhibitors blocking pathways like PD-1/PD-L1 and CTLA-4 have pioneered this approach, alongside diverse strategies including monoclonal antibodies such as trastuzumab and cetuximab, bispecific antibodies like blinatumomab and teclistamab, antibody-drug conjugates including brentuximab vedotin and trastuzumab emtansine, CAR-T and CAR-NK engineered cells, mRNA vaccines, and emerging technologies like oncolytic viruses and exosomes targeting the tumor microenvironment. Despite these advances making immunotherapy a cornerstone of modern cancer treatment, significant clinical challenges limit widespread adoption. Response rates vary considerably, ranging from twenty to forty percent with checkpoint inhibitors to fifty to ninety percent with CAR-T cells and seventy-three percent with CAR-NK cells. Additionally, patients face primary resistance, secondary resistance following initial response, and hyper-progressive disease occurring in ten to thirty percent of cases. Identifying predictive biomarkers for immunotherapy response is critical for overcoming treatment resistance, minimizing immune-related adverse events, and enabling personalized treatment strategies that optimize outcomes while reducing unnecessary exposure to ineffective therapies.

Despite significant therapeutic advances including CDK4/6 inhibitors and antibody-drug conjugates for hormone receptor-positive, HER2-low metastatic breast cancer, real-world treatment patterns reveal persistent clinical challenges. A retrospective analysis of 2,662 patients with metastatic HR-positive, HER2-low disease from the Flatiron Health Research Database (diagnosed 2018-2023) examined treatment patterns across five lines of therapy. First-line treatment remained predictable, with 86.2% receiving endocrine therapy-containing regimens, predominantly ET plus CDK4/6 inhibitors (57.1%), while adoption of CDK4/6 inhibition increased from 51.9% to 60.7% between 2017-2023. However, critical findings emerged after progression: endocrine-containing regimens progressively declined from 86.2% in the first line to 50.3% by the fifth line, reflecting progressive endocrine resistance. This pattern illustrates a fundamental problem in metastatic breast cancer management—as endocrine options become exhausted through repeated exposure, treatment becomes increasingly heterogeneous, chemotherapy use rises, and disease control shortens dramatically. These findings underscore the urgent clinical need for alternative therapeutic strategies beyond traditional endocrine approaches in this patient population.

Moderna and its collaborators announced promising results from a phase III clinical trial demonstrating that a personalized mRNA cancer vaccine significantly reduced melanoma recurrence risk. This vaccine represents a landmark achievement as the first mRNA-based cancer treatment to show success in a late-stage trial, leveraging the same mRNA technology platform that enabled rapid COVID-19 vaccine development. The personalized approach tailors the vaccine to individual patients' tumor mutations, potentially offering a more targeted therapeutic strategy. This breakthrough holds substantial significance for oncology, as it validates mRNA technology's application beyond infectious diseases and opens new therapeutic pathways for cancer treatment. The success could accelerate development of similar mRNA-based vaccines for other cancer types and establish a new paradigm for precision medicine in oncology. The trial outcomes suggest mRNA vaccines may play an increasingly important role in preventing cancer recurrence and improving patient outcomes, marking a pivotal moment in the intersection of immunotherapy and personalized medicine.

Obecabtagene autoleucel, a CD19-directed autologous CAR T-cell therapy, demonstrated significantly superior efficacy compared with standard treatments for relapsed or refractory B-cell acute lymphoblastic leukemia in adults. The propensity score-matched analysis of the phase 1b/2 FELIX trial (107 patients) showed overall remission rates of 67.3% versus 51.4% in matched controls receiving blinatumomab, inotuzumab ozogamicin, or chemotherapy. In the modified intent-to-treat population, remission rates reached 79.8% compared with 54.8% in controls. Median overall survival favored CAR T-cell therapy at 15.1 months with transplant censoring versus 7.0 months with standard care, while median event-free survival was 9.8 months versus 2.5 months. Safety profiles remained comparable between groups. These results, published in Leukemia, suggest obecabtagene autoleucel addresses significant clinical needs in this high-risk population where outcomes with conventional therapies remain poor.

This Frontiers in Immunology review examines in vivo CAR T-cell generation, a promising approach that engineers T cells directly within the patient's body rather than through traditional ex vivo manufacturing. Authored by Huo, Yao, and Kong, the article evaluates emerging delivery platforms essential for clinical translation, particularly lentiviral vectors and lipid nanoparticles, which serve as critical vehicles for introducing CAR-encoding genetic material into patient lymphocytes. The review synthesizes current clinical progress in this field while identifying significant translational barriers that must be overcome for widespread therapeutic adoption. By analyzing both established and novel gene delivery systems, the authors provide comprehensive insights into optimizing in vivo CAR T-cell therapy's efficacy and safety. This work matters substantially because in vivo approaches could circumvent manufacturing bottlenecks, reduce costs, and accelerate treatment availability for cancer patients, while the identified barriers inform future research priorities aimed at realizing this technology's full clinical potential.

Complicated urinary tract infections (cUTIs) present escalating clinical challenges as antimicrobial resistance increasingly compromises treatment efficacy. These infections involve resistant uropathogens, recurrent episodes, urinary tract abnormalities, catheterization, and comorbidities that drive poor outcomes and treatment failures. Recent advances have deepened understanding of molecular resistance mechanisms, bacterial adaptation, biofilm formation, and host-pathogen interactions, while rapid diagnostics and genomic surveillance technologies promise more targeted antimicrobial selection. However, significant implementation gaps persist between research discoveries and clinical practice. Critical unresolved questions include optimal definitions of cUTIs, ideal therapy duration and routes, combination treatment protocols, and diagnostic stewardship strategies to minimize unnecessary antimicrobial exposure. This Research Topic addresses these complexities by examining biological, diagnostic, and therapeutic dimensions of resistant cUTIs. It seeks studies investigating resistance emergence and transmission, factors contributing to treatment failure, and approaches enhancing diagnostic accuracy and antimicrobial decision-making. The initiative also explores innovative non-traditional therapies, including bacteriophage-based interventions, alongside conventional antimicrobials. By integrating clinical microbiology, infectious disease, and urology perspectives, this collaborative effort aims to establish evidence-based management strategies for patients with resistant uropathogens.

# Professional Summary This comprehensive review examines the immunological mechanisms distinguishing "cold" tumors, characterized by low immune infiltration and poor immunotherapy response, from "hot" tumors with robust anti-tumor immunity. The authors analyze dysregulation within the cancer-immunity cycle—the sequential steps through which the immune system recognizes and eliminates cancer cells—identifying key checkpoints where this cycle breaks down in cold tumors. The article explores how immunosuppressive factors, tumor microenvironment characteristics, and immune evasion strategies contribute to this dichotomy. Critically, the review evaluates emerging nanotechnology-driven therapeutic approaches designed to convert cold tumors into immunologically active hot tumors. These nano-based strategies include targeted drug delivery systems, nanoparticle-mediated immune activation, and combination therapies enhancing checkpoint inhibitor efficacy. Understanding these immunological determinants and developing effective interventions matters significantly for improving outcomes in patients with treatment-resistant cancers and expanding immunotherapy applicability beyond currently responsive tumor types.

Researchers have developed an innovative "micro-bladder" model to investigate why urinary tract infections persist despite antibiotic treatment. This flowing tissue-engineering system mimics the dynamic conditions within the human bladder, revealing that bacteria survive in ways standard laboratory susceptibility tests cannot detect. The micro-bladder demonstrates how pathogens evade apparently appropriate antibiotics, explaining the clinical reality faced by millions of patients, particularly women experiencing recurrent UTIs where symptoms return weeks or months after treatment. By simulating actual bladder physiology rather than static in vitro conditions, this device provides critical insights into bacterial survival mechanisms and treatment resistance. The findings have significant implications for developing more effective UTI therapies and improving clinical outcomes for patients with chronic infections who currently face incomplete pictures from conventional diagnostic methods.

This comprehensive analysis examines T-cell redirecting therapies as emerging treatment approaches for lung cancer. The research reviews clinical trial data on three primary therapeutic modalities: bispecific T-cell engagers (BiTEs), chimeric antigen receptor T (CAR-T) cell therapy, and TCR-engineered T cells, alongside tumor-infiltrating lymphocyte (TIL) strategies. These immunotherapies work by redirecting and activating patients' own T cells to recognize and eliminate cancer cells. The study synthesizes evidence from multiple clinical trials to evaluate the efficacy, safety profiles, and clinical outcomes of these approaches in lung cancer patients. This analysis matters significantly as T-cell redirecting therapies represent a paradigm shift in oncology, offering potential alternatives or complements to conventional treatments. Understanding their performance across diverse trial settings provides critical insights for clinicians and researchers evaluating treatment options and informs future development of optimized immunotherapeutic strategies for this disease.

Cancer treatment is increasingly shifting toward personalized approaches that harness the immune system's power. A landmark clinical trial demonstrates that combining Moderna and Merck's experimental mRNA vaccine intismeran with Merck's established immunotherapy pembrolizumab (Keytruda) significantly outperforms Keytruda alone in treating melanoma. The study enrolled 1,137 patients with stage 2 to 4 melanoma who underwent surgery, then received either the combination therapy or Keytruda monotherapy for over a year. Patients receiving both treatments experienced longer recurrence-free survival and fewer instances of cancer spread. Intismeran represents a novel autogene therapy that analyzes individual tumor mutations, generates personalized mRNA sequences encoding those mutations, and administers them as a therapeutic vaccine to train the immune system to recognize cancer cells. The mRNA platform's key advantage lies in its rapid sequence generation capability—achievable within weeks—enabling scalable personalized cancer treatment. While Keytruda works by exposing hidden cancer cells to immune detection, intismeran teaches the immune system to identify tumor-specific mutations. Though intismeran remains unapproved, these results suggest that combining personalized mRNA vaccines with checkpoint inhibitors represents a promising therapeutic strategy for melanoma management.

The Neo-CheckRay trial, a randomized Phase 2 study published in Nature Medicine, investigated whether radiation could enhance immunotherapy sensitivity in estrogen receptor-positive, HER2-negative breast cancer, a traditionally immune-cold tumor type with limited immunotherapy benefit. Researchers led by Alex De Caluwé evaluated neoadjuvant immune-modulating stereotactic body radiation therapy (iSBRT) combined with chemotherapy, with or without the PD-L1 inhibitor durvalumab and CD73 inhibitor oleclumab, in women with high-risk early-stage disease. While the trial did not achieve its primary endpoint of significantly improving residual cancer burden 0/1 response rates, it revealed a counterintuitive finding: the greatest benefit from checkpoint inhibition appeared in PD-L1-negative tumors, a subgroup conventionally considered less responsive to immunotherapy. This contrasts with prior Phase 3 trials like KEYNOTE-756 and CheckMate 7FL, which showed modest pCR improvements with standard immune checkpoint blockade. Neo-CheckRay's novel approach attempted to reprogram the tumor microenvironment through radiation-induced immune modulation, addressing the fundamental challenge of immune suppression in ER-positive/HER2-negative disease and potentially redefining patient selection for immunotherapy in this population.

Merck and Moderna announced positive Phase 3 results from the INTerpath-001 trial evaluating intismeran autogene, a personalized neoantigen immunotherapy, combined with Merck's KEYTRUDA (pembrolizumab) in patients with completely resected stage IIB-IV melanoma. The combination met both primary endpoints, demonstrating statistically significant improvements in recurrence-free survival and distant metastasis-free survival compared to KEYTRUDA monotherapy. Intismeran autogene is a therapeutic cancer vaccine designed to activate the immune system against patient-specific tumor mutations. The trial involved melanoma patients at high risk of recurrence following surgical resection. These results represent a significant advancement in adjuvant melanoma treatment, potentially establishing the personalized vaccine plus checkpoint inhibitor approach as a new standard of care. The positive findings underscore the therapeutic potential of combining individualized neoantigen vaccines with immunotherapy, offering promise for improving long-term outcomes in high-risk melanoma patients and potentially informing strategies in other cancer types.

Le changement climatique est aujourd’hui reconnu comme une menace majeure pour la santé publique. Paradoxalement, le secteur de la santé, conçu pour soigner et prévenir les maladies, contribue lui-même à ce problème : il représente environ 5 % des émissions mondiales de gaz à effet de serre, avec des chiffres pouvant atteindre 10 % dans certains pays industrialisés. Parmi les activités médicales, l’imagerie occupe une place importante : on estime qu’elle contribue à près de 10 % de l’empreinte carbone des systèmes de santé.