PubMed

(tuberculosis[Title/Abstract]) OR (lung cancer [Title/ Abstract])

Filters applied: from 2025/7/1 - 2025/7/31.

1. J Thorac Oncol. 2025 Jul;20(7):884-896. doi: 10.1016/j.jtho.2025.02.013. Epub 2025 Feb 13.

Overdiagnosis of Lung Cancer Due to the Introduction of Low-Dose Computed Tomography in Average-Risk Populations in the People's Republic of China.

INTRODUCTION: Low-dose computed tomography (LDCT) has been widely used in health check-ups in China since 2011. The introduction of LDCT in average-risk populations may have led to substantial overdiagnosis of lung cancer.

METHODS: This registry-based study included 46,978 incident cases and 34,475 deaths of lung cancer derived from a population of approximately 3.21 million in the Pudong New Area of Shanghai, People's Republic of China, from 2002 to 2020. We calculated the age-standardized rates of overall, stage- and histology-specific incidence and overall mortality by sex. The numbers and proportions of cases attributable to overdiagnosis were estimated on the basis of the comparison between the shape of the age-specific curve with that before the introduction of LDCT in average-risk populations since 2011.

RESULTS: The age-standardized incidence of lung cancer increased rapidly since 2011 in both male and female individuals, whereas the age-standardized mortality declined over the period. The upward trends in incidence were mainly observed in women with early-stage cancer and lung adenocarcinoma. Overall, no significant overdiagnosis was observed in men, whereas the overdiagnosis rate grew from 22% in 2011 to 2015 to 50% in 2016 to 2020 in women. Further analysis reported elevated numbers (proportions) of lung adenocarcinoma cases attributable to overdiagnosis, which rose from 182 cases (8%) in 2011 to 2015 to 827 cases (22%) in 2016 to 2020 in men, and from 1842 cases (85%) to 4171 cases (89%) in women.

CONCLUSION: This study demonstrates considerable and increasing overdiagnosis of lung adenocarcinoma in Chinese men and women. The guideline is urgently needed to maximize the benefits of LDCT screening and reduce the potential overdiagnosis of lung cancer.

PMID: 39954810 [Indexed for MEDLINE]

2. Nat Microbiol. 2025 Aug;10(8):2073-2091. doi: 10.1038/s41564-025-02050-3. Epub 2025 Jul 14.

A single-cell transcriptomic atlas reveals senescence and inflammation in the post-tuberculosis human lung.

Patients with a history of Mycobacterium tuberculosis infection often suffer from irreversible and progressive pulmonary damage, yet the underlying mechanisms are not fully understood. Here we conducted single-cell transcriptomic analysis of human lung tissues including 19 post-tuberculosis lung tissues and 13 matched normal lung samples as controls, focusing on areas within and surrounding tuberculosis lesions. We identified tuberculosis-associated molecular signatures across various cell types, including gene expression patterns associated with senescence, inflammation, fibrosis and apoptosis. We observed increased vascular inflammation as a key feature of lung tissues following tuberculosis. Signatures of decreased FOXO3 signalling and increased NF-κB-dependent thromboinflammation were validated by showing that small interfering RNA silencing of FOXO3 and thrombin treatment exacerbated senescence and inflammation in pulmonary endothelial cells. These findings provide insight into the mechanisms contributing to post-tuberculosis pulmonary damage and suggest potential therapeutic targets for alleviating lung impairment in these patients.

PMID: 40659921 [Indexed for MEDLINE]

3. Cancer Res. 2025 Jul 2;85(13):2429-2447. doi: 10.1158/0008-5472.CAN-24-3481.

Chronic Stress Stimulates Protumor Macrophage Polarization to Propel Lung Cancer Progression.

Chronic psychologic stress is often associated with manifestations of malignant diseases. Identification of modulators regulating the interaction between stress and tumorigenesis could provide potential strategies to ameliorate cancer progression. In this study, we observed that chronic stress markedly promoted lung cancer progression. Analysis of the landscape of long noncoding RNA expression indicated that long noncoding RNA HIF1A-AS3 was upregulated in the stressed group and in lung cancer specimens compared with normal tissues. HIF1A-AS3 promoted the proliferation and invasion of lung cancer cells both in vitro and in vivo. Mechanistically, HIF1A-AS3 translationally activated hypoxia-inducible factor-1α (HIF1α) via direct interaction with YBX1, stimulating downstream signaling cascades. HIF1α inversely stimulated HIF1A-AS3 transcription by directly binding to its promoter region. Investigation of the immune microenvironment revealed that macrophage depletion could efficiently abolish the tumor-promoting effects of chronic stress. Both chronic stress and HIF1A-AS3 overexpression induced M2-like macrophage polarization in tumor tissues in mice. Conditioned medium from HIF1A-AS3-overexpressing lung cancer cells enhanced the macrophages mobility. Macrophages exhibited suppressed phagocytic activity against HIF1A-AS3-overexpressing tumor cells. Targeting HIF1A-AS3/HIF1α signaling, which was aberrantly upregulated in human lung cancer specimens and predictive of poor prognosis, counteracted chronic stress-induced lung cancer progression in vivo. In conclusion, the HIF1A-AS3/HIF1α positive feedback loop mediates chronic stress-induced lung cancer growth through functional reprogramming of tumor-associated macrophages, suggesting that this axis may serve as a promising diagnostic and therapeutic target for patients with lung cancer suffering from psychologic stress.

SIGNIFICANCE: Chronic stress facilitates lung cancer immune evasion by inducing M2-like macrophage polarization, supporting the potential of combination therapies targeting both tumor cells and the immune microenvironment for treating stress-related cancers.

PMID: 40202818 [Indexed for MEDLINE]

4. Lancet Infect Dis. 2025 Jul;25(7):e432-e438. doi: 10.1016/S1473-3099(25)00083-0. Epub 2025 Mar 22.

Tuberculosis preventive therapy: scientific and ethical considerations for trials of ultra-short regimens.

Preventive therapy remains key to the elimination of tuberculosis and is typically offered to people with presumptive Mycobacterium tuberculosis infection to prevent active disease. Although the duration of tuberculosis preventive therapy has been reduced substantially over time, it remains long in absolute terms, and uptake remains low. Treatment-shortening trials using non-inferiority designs have so far led to the implementation of effective regimens of 1-4 months' duration. Such regimens are a substantial improvement on the previous 6-9 months' duration standard of care but still far too long given potential toxicity and the very low baseline risk of disease for most individuals. The efficacy of even shorter tuberculosis preventive therapy regimens, including ultra-short regimens shorter than 2 weeks' duration, is yet to be explored, but optimal public health outcomes might be achieved even if the efficacy of such regimens is lower than that of the standard of care. Greater acceptability could lead to higher population uptake, and, potentially, to more cases of tuberculosis avoided. Nonetheless, the optimal duration of ultra-short tuberculosis preventive therapy regimens cannot be explored through classic two-arm non-inferiority trials. Instead, the relationship between different durations and efficacy of tuberculosis preventive therapy will need to be characterised, requiring some participants to be randomly assigned to no (or delayed) therapy in order to characterise the number of tuberculosis cases averted by the shortest options. We argue that such trials are needed to identify the optimal trade-off between efficacy and acceptability and would be ethically acceptable provided there were appropriate risk mitigation measures for participants, including careful monitoring for the development of active disease. In this Personal View, we discuss some of the scientific and ethical considerations around the investigation of ultra-short-course preventive therapy for tuberculosis.

PMID: 40127669 [Indexed for MEDLINE]

5. Adv Sci (Weinh). 2025 Jul 18: e08878. doi: 10.1002/advs.202508878. Online ahead

of print.

Prediction of Lung Cancer Metastasis Risk Based on Single-Cell Metabolic Profiling of Circulating Tumor Cells.

Lung cancer metastasis is a leading cause of cancer-related mortality, necessitating innovative approaches for early prediction and personalized clinical management. A novel strategy is present to predict lung cancer metastasis risk by combining single-cell metabolic profiling of circulating tumor cells (CTCs) with a self-developed CTC sorting and capture platform, enabling high-efficiency, high-viability CTC isolation from blood. Using nanoelectrospray ionization-atmospheric pressure chemical ionization mass spectrometry, single-cell metabolomic profiling on 301 CTCs derived from patients and animal models are performed. 390 unique metabolites are identified and discovered distinct metabolic signatures associated with different metastatic potentials (brain and bone). Based on these metabolic profiles, a classification model that categorizes CTCs into subgroups with distinct metastatic risks are constructed. The model outperformed traditional clinical indicators and total CTC counts, achieving AUCs of 0.74 (brain metastasis) and 0.92 (bone metastasis). Prospective validation confirmed its metabolite-based classification accuracy for one-year metastasis risk prediction. This study highlights the potential of single-cell metabolomics to uncover novel therapeutic targets and prognostic markers, advancing liquid biopsy from quantitative counting to qualitative analysis. The approach represents a significant advancement in precision medicine for lung cancer management, offering a personalized strategy for predicting metastasis risk and guiding clinical treatment.

PMID: 40679062

6. J Thorac Oncol. 2025 Jul;20(7):871-883. doi: 10.1016/j.jtho.2025.01.019. Epub 2025 Jan 24.

Lung Cancer Screening Program Quality Indicators-Review and Recommendations: An International Association for the Study of Lung Cancer Delphi Process Study.

INTRODUCTION: Lung cancer screening (LCS) using low-dose-computed tomography reduces lung cancer mortality in high-risk individuals. Evaluating and monitoring LCS programs are important to ensure and improve quality, efficiency, and participant outcomes. There is no agreement on LCS quality indicators (QIs).

METHODS: Twenty multidisciplinary members of the International Association for the Study of Lung Cancer used a Delphi process to develop consensus QIs. They considered 50 QIs during information/discussion sessions and two anonymous voting rounds. In total, 80% or more voting agree or strongly agree on a five-point Likert scale determined consensus.

RESULTS: Twenty essential and six desirable QIs were identified in 10 of 11 LCS pathway domain categories (ENTRY: Proportion eligible who got screened; SMOKING_CESSATION: Proportion of current-smoking individuals offered cessation interventions; IMAGING: Proportion screened requiring clinical diagnostic assessment, scan results distribution, proportion scans requiring early follow-up, proportion baseline or regular scans with actionable additional findings; ADHERENCE to: Annual or regular scans, early interim scans, clinical diagnostic assessment; DIAGNOSTIC: Proportion suspicious-for-lung-cancer scans receiving clinical investigation, undergoing invasive diagnostic procedures;

OUTCOMES: Cancer detection rate, stage distribution, interval cancer rate; HARMS: Number and proportion of serious complications after invasive procedures, non-lung cancer diagnoses after invasive procedures or surgery, 30-day mortality after invasive procedure; TREATMENT: Proportion early-stage cancers receiving treatment with curative intent; WAIT_TIMES: Suspicious-for-lung-cancer scan to definitive diagnosis, to curative-intent treatment for individuals with early-stage disease, scan completion to reporting results to primary care provider and participant; EQUITY: Race, sex, and socioeconomic differences in adherence to regular screens, early-stage cancer treatment, offer of smoking cessation interventions, clinical investigation of suspicious-for-lung-cancer screens).

CONCLUSIONS: A review among panel members provided recommended LCS QIs that should be considered in the development of LCS initiatives.

PMID: 39864549 [Indexed for MEDLINE]

7. Nat Commun. 2025 Jul 1;16(1):5608. doi: 10.1038/s41467-025-60730-4.

Ghrelin-induced neuronal NPY promotes brain metastasis in lung cancer patients with low BMI.

Obesity is a known risk factor for many cancers, yet recent studies reveal a paradoxical association between low body mass index (BMI) and increased brain metastasis in lung cancer-referred to as the "obesity paradox," with unclear molecular mechanism(s). Here, we show a significantly higher incidence of brain metastasis in low-BMI lung cancer patients compared to those with high-BMI or other cancer brain metastasis in a pan-analysis of 7628 patients. Mechanistically, low BMI activates ghrelin-GHSR signaling, increasing neuronal neuropeptide Y (NPY) secretion, which promotes tumor metabolic reprogramming via NPY-Y5R, facilitating brain colonization. Elevated plasma ghrelin levels in cancer-free low-BMI subjects suggest its potential as a prognostic biomarker for predicting brain metastasis. Notably, targeting NPY-Y5R or reversing low BMI effectively suppresses brain metastasis, supporting its pro-metastatic role. These findings provide a strong rationale for developing targeted interventions to treat or prevent brain metastasis in lung cancer patients with low BMI.

PMID: 40595538 [Indexed for MEDLINE]

8. Adv Sci (Weinh). 2025 Jul 28: e02626. doi: 10.1002/advs.202502626. Online ahead of print.

Clinical Features, Molecular Biology, and the Metastatic Microenvironment in Lung Cancer Brain Metastases: Implications for Treatment Decisions.

Brain metastases (BM) represent a highly aggressive, clinically distinct subtype of lung cancer, often associated with poor prognosis. Historically, treatment options for BM have been limited and largely nonspecific. However, recent advancements in clinical and preclinical research have led to substantial improvements in patient outcomes. This review focuses on BM arising from lung cancer, providing an overview of recent findings related to clinical characteristics, diagnostic strategies, and early metastatic processes. Multi-omics analyses have elucidated the molecular mechanisms underlying tumor initiation and progression, with particular emphasis on the role of the tumor microenvironment. In this review, preclinical BM models, detailed signaling pathways, and emerging clinical therapies are also discussed. Current treatment approaches are multidisciplinary, and multi-omics technologies enhance both diagnosis and therapeutic strategies by revealing the complex biology of BM. Continued research is needed to identify BM-specific drug targets, particularly those involved in crossing the blood-brain barrier and remodeling the brain microenvironment. Addressing these challenges is crucial for improving clinical outcomes in patients with BM.

PMID: 40719284

9. CA Cancer J Clin. 2025 Jul 17. doi: 10.3322/caac.70024. Online ahead of print.

Personalized care for patients with EGFR-mutant nonsmall cell lung cancer: Navigating early to advanced disease management.

The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene has revolutionized the management of lung cancer, enabling the development of targeted tyrosine kinase inhibitors (TKIs). These therapies offer improved survival and reduced side effects compared with conventional treatments. Recent advancements have significantly reshaped the treatment paradigm for EGFR-mutant non-small cell lung cancer. TKIs are now incorporated into the management of early stage and locally advanced disease, and phase 3 trials have explored combination strategies in metastatic settings. Although these intensified approaches improve progression-free survival, they come with increased toxicity and higher costs, underscoring the need for precise patient

selection to maximize benefit. Emerging data on biomarkers, such as co-mutations and circulating tumor DNA, show promise for refining treatment decisions. In addition, significant progress in understanding resistance mechanisms to EGFR TKIs has broadened therapeutic options. This review provides a comprehensive overview of the current landscape of EGFR-mutant nonsmall cell lung cancer, highlighting recent breakthroughs and discussing strategies to optimize treatment based on the latest evidence.

PMID: 40673977

10. Ann Oncol. 2025 Jul;36(7):786-795. doi: 10.1016/j.annonc.2025.03.013. Epub 2025 Mar 31.

Lung cancer detection by electronic nose analysis of exhaled breath: a multicentre prospective external validation study.

BACKGROUND: Electronic nose (eNose) analysis of exhaled breath shows potential for accurate and timely lung cancer diagnosis, yet prospective external validation studies are lacking. Our study primarily aimed to prospectively and externally validate a published eNose model for lung cancer detection in chronic obstructive pulmonary disease (COPD) patients and assess its diagnostic performance alongside a new eNose model, specifically tailored to the target population, in a more general outpatient population.

PATIENTS AND METHODS: This multicentre prospective external validation study included adults with clinical and/or radiological suspicion of lung cancer who were recruited from thoracic oncology outpatient clinics of two sites in the Netherlands. Breath profiles were collected using a cloud-connected eNose (SpiroNose®). The diagnostic performance of the original and new eNose models was assessed in various population subsets based on receiver operating characteristic-area under the curve (ROC-AUC), specificity, positive predictive value (PPV), and negative predictive value (NPV), targeting 95% sensitivity. For the new eNose model, a training cohort and a validation cohort were used.

RESULTS: Between March 2019 and November 2023, 364 participants were included. The original eNose model detected lung cancer with an ROC-AUC of 0.92 [95% confidence interval (CI) 0.85-0.99] in COPD patients (n = 98/116; 84%) and 0.80 (95% CI 0.75-0.85) in all participants (n = 216/364; 59%). At 95% sensitivity, the specificity, PPV, and NPV, were 72% and 51%, 95% and 74%, and 72% and 88%, respectively. In the validation cohort, the new eNose model identified lung cancer across all participants (n = 72/121; 60%) with an ROC-AUC of 0.83 (95% CI 0.75-0.91), sensitivity of 94%, specificity of 63%, PPV of 79%, and NPV of 89%. Notably, accurate detection was consistent across tumour characteristics, disease stage, diagnostic centres, and clinical characteristics.

CONCLUSION: This multicentre prospective external validation study confirms that eNose analysis of exhaled breath enables accurate lung cancer detection at thoracic oncology outpatient clinics, irrespective of tumour characteristics, disease stage, diagnostic centre, and clinical characteristics.

PMID: 40174676 [Indexed for MEDLINE]

11. Eur Respir J. 2025 Jul 24;66(1):2402000. doi: 10.1183/13993003.02000-2024. Print 2025 Jul.

How to diagnose TB in migrants? A systematic review of reviews and decision tree analytical modelling exercise to evaluate properties for single and combined tuberculosis screening tests.

Comment in

    Eur Respir J. 2025 Jul 24;66(1):2500750. doi: 10.1183/13993003.00750-2025.

BACKGROUND: Optimising tuberculosis disease testing algorithms is fundamental to ensuring the effectiveness and cost-effectiveness of migrant screening programmes, including better understanding of individual and combined screening test properties. The aim of our study was to estimate pooled tuberculosis test properties from the literature and combine them in decision analytical modelling with a focus on whether tests used for the diagnosis of tuberculosis infection might add value to these algorithms.

METHODS: We performed a systematic review of reviews of diagnostic tests for active tuberculosis, searching PubMed, Embase, Web of Science and Cochrane library, and pooled test properties extracted from original papers included in reviews. We used these pooled results in a decision tree analysis to estimate test properties for common migrant screening algorithms.

RESULTS: We retrieved 1477 records and included 32 reviews, including data from 437 original studies for 18 tuberculosis tests, providing pooled results for 13. Our modelling showed that algorithms with interferon-γ release assays had the highest diagnostic odds ratios (dORs) (e.g. QuantiFERON/chest X-ray (for tuberculosis abnormalities)/Xpert dOR 24 670, 95% CI 11 630-52 328) and high positive predictive values. Best sensitivities were achieved for combinations with parallel cough/chest X‑ray screening followed by Xpert (0.88, 95% CI 0.86-0.90) or Ultra (0.92, 95% CI 0.90-0.94) as well as by T-Spot.TB followed by parallel symptom/chest X-ray screening and Ultra (0.81, 95% CI 0.78-0.83) or Xpert (0.77, 95% CI 0.75-0.80).

CONCLUSIONS: The significant test accuracy benefit of adding interferon-γ release assays to an active tuberculosis screening pathway will help inform clinicians and policy-makers on the most effective screening algorithms.

PMID: 40268506 [Indexed for MEDLINE]

12. Signal Transduct Target Ther. 2025 Jul 10;10(1):218. doi: 10.1038/s41392-025-02301-z.

Targeting CD155 in lung adenocarcinoma: A5 nanobody-based therapeutics for precision treatment and enhanced drug delivery.

This study presents a novel approach targeting CD155, an overexpressed protein in lung adenocarcinoma (LUAD), using nanobodies with exceptional precision and efficacy. The significant upregulation of CD155 in LUAD, associated with poor patient outcomes, highlights its potential as a therapeutic target. An anti-CD155 nanobody (A5 Nb) is developed that binds to CD155-positive lung cancer cells with high affinity (A5 Nb Kd = 0.23 nM). The complementarity-determining region of A5 Nb forms hydrophobic interactions and hydrogen bonds with CD155, promoting selective binding and stabilization of A5 Nb-CD155 complex. This interaction inhibits focal adhesion signaling by downregulating paxillin (PXN), leading to a >50% reduction in cell migration. Additionally, A5 Nb conjugated to liposomes loaded with doxorubicin (A5-LNP-DOX) demonstrates a 2- to 3-fold increase in uptake and cytotoxicity in CD155-positive A549 cells, suggesting its potential as a targeted drug delivery system. Therapeutic efficacy was further validated in both lung orthotopic mouse models and lung cancer organoid xenografts, where A5-LNP-DOX exhibited robust antitumor effects and selective targeting. The CD155-PXN axis emerges as a clinically relevant target, correlating with poor outcomes in patients with lung cancer. This study highlights the therapeutic potential of A5 nanobodies in targeting CD155-overexpressing lung cancer cells and offers insights for future developments in lung cancer therapeutics.

PMID: 40634277 [Indexed for MEDLINE]

13. J Thorac Oncol. 2025 Jul;20(7):847-855. doi: 10.1016/j.jtho.2025.03.030.

Reducing Lung Cancer Mortality by Providing Smoking Cessation Support in the Lung Cancer Screening Setting: Missed Opportunities and Lessons Learned on Both Sides of the Atlantic.

National guidelines for the implementation of lung cancer screening (LCS) for high-risk older adults have been issued by several countries, largely in Europe, North America, and Australia. Typically, these guidelines recommend but do not specify how smoking cessation support (SCS) should be provided to patients undergoing LCS who currently smoke. As LCS implementation progresses, delivering screening to the millions of eligible individuals around the world, the lack of best practice guidelines for SCS in the LCS setting is resulting in a growing missed opportunity to reduce persistent tobacco and lung cancer-related disparities in incidence and mortality. Quitting smoking at older ages reduces lung cancer risk and increases life expectancy. Compelling evidence from clinical trials and modeling studies has shown that, even with modest cessation rates, SCS delivered in the LCS setting can considerably reduce lung cancer mortality, with the potential to reduce global, racial, economic, and geographic disparities in lung cancer. Moreover, SCS interventions are cost-effective and can lead to significant cost savings for the health system. On the basis of the evidence and lessons learned in the United Kingdom, Canada, and the United States, we propose a set of priorities for health systems to consider when developing or expanding SCS programs in the LCS setting. We argue that the system and policy changes needed to maintain SCS as a standard component of LCS are essential to capitalize on this important opportunity to integrate disease prevention with early detection, thereby maximizing the mortality benefit of LCS worldwide.

PMID: 40617668 [Indexed for MEDLINE]

14. Lancet Glob Health. 2025 Jul;13(7): e1240-e1249. doi: 10.1016/S2214-109X (25)00114-7.

Implications of progressive lung damage and post-tuberculosis sequelae for the health benefits of prompt tuberculosis treatment in high HIV prevalence settings: a mathematical modelling analysis.

Update of

    medRxiv. 2024 Aug 17:2024.08.12.24311198. doi: 10.1101/2024.08.12.24311198.

BACKGROUND: Untreated pulmonary tuberculosis causes ongoing lung damage, which can persist after treatment. Conventional modelling approaches for assessing tuberculosis health effects might not fully capture these mechanisms. We evaluated how tuberculosis-associated lung damage and post-tuberculosis sequelae affect the lifetime health consequences of tuberculosis in high HIV prevalence settings.

METHODS: We developed a microsimulation model (computer simulations that reproduce disease natural history and intervention effects for sampled individuals) representing dynamic changes in lung function for individuals evaluated for tuberculosis in routine clinical settings. We parametrised the model with data (from a previously published study) for three African countries with a high burden of tuberculosis and HIV: Uganda, Kenya, and South Africa, and estimated lifetime health outcomes under prompt, delayed, and no tuberculosis treatment scenarios. We compared results to earlier modelling approaches that omit progressive lung damage and post-tuberculosis sequelae.

FINDINGS: We estimated a 5·1 years (95% uncertainty interval 3·8-6·4) reduction in life expectancy due to tuberculosis with prompt treatment, 7·7 years (5·5-10·1) with delayed treatment, and 18·5 years (15·5-20·6) with no treatment. Estimated per-person disability-adjusted life-years (DALYs) from tuberculosis were 11·4 years (8·9-14·2) with prompt treatment, 17·1 years (13·1-22·1) with delayed treatment, and 37·7 years (34·3-40·3) with no treatment. Compared with individuals without HIV, individuals with HIV had a greater proportion of tuberculosis-attributable deaths, but fewer life-years lost to tuberculosis. Post-tuberculosis DALYs represented 52·5% of total DALYs with prompt treatment, 42·7% with delayed treatment, and 9·1% with no treatment. Modelling approaches that omit progressive lung damage and post-tuberculosis sequelae underestimated lifetime health losses of tuberculosis by 48-57% and underestimated the benefits of prompt treatment by 45-64%.

INTERPRETATION: Delayed initiation of tuberculosis treatment causes greater lung damage and higher mortality risks during and after the disease episode than prompt treatment. In settings with coprevalent tuberculosis and HIV, accounting for these factors substantially increased estimates of the lifetime disease burden and life expectancy loss caused by tuberculosis. These findings imply greater health effects and cost-effectiveness for interventions to prevent tuberculosis and achieve earlier treatment initiation than indicated in previous analytical approaches.

FUNDING: US National Institutes of Health.

PMID: 40580989 [Indexed for MEDLINE]

15. Lancet Infect Dis. 2025 Jul;25(7):764-774. doi: 10.1016/S1473-3099(24)00816-8. Epub 2025 Feb 6.

Effects of conditional cash transfers and pre-test and post-test tuberculosis counselling on patient outcomes and loss to follow-up across the continuum of care in South Africa: a randomised controlled trial.

BACKGROUND: Economic and behavioural factors lead to poor outcomes in patients with tuberculosis. We investigated the effects of a package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers on patient outcomes in adults undergoing investigation for pulmonary tuberculosis.

METHODS: This pragmatic, open-label, individual randomised controlled trial was done in nine clinics in Johannesburg, South Africa. Participants (aged ≥18 years) undergoing investigation for tuberculosis were randomly assigned (1:1) to the intervention group or control group (standard of care) via permuted block randomisation, stratified by clinic; group assignment was concealed using opaque envelopes. The intervention group received pre-test and post-test tuberculosis counselling, and for participants diagnosed with rifampicin-susceptible tuberculosis, a digital payment (R150; approximately US$10) at treatment initiation and each monthly treatment visit. Payments were contingent on timely attendance: 14 days from initial sputum sample collection and within 7 days on either side of their scheduled monthly appointment. The primary endpoint was successful patient outcome (patients who were cured or completed treatment) or unsuccessful patient outcome (pretreatment loss-to-follow-up, on-treatment loss-to-follow-up, development of rifampicin-resistant tuberculosis while on treatment, treatment failure [ie, smear or culture positive at 5 months or later after commencing treatment], or death). The primary outcome was analysed in the modified intention-to-treat population, defined as all randomly assigned participants with rifampicin-susceptible tuberculosis confirmed before the commencement of tuberculosis treatment. Weighted outcome prevalence, relative risks (RRs), and risk differences were calculated using a multivariable Poisson model with robust standard errors. This trial is registered with the Pan African Clinical Trials Registry (PACTR202410708311054) and is completed.

FINDINGS: Between Oct 25, 2018, and Dec 9, 2019, 4110 participants were enrolled and randomly assigned, 2059 to the intervention group and 2051 to the control group. 381 (9·3%) participants had microbiologically confirmed rifampicin-susceptible pulmonary tuberculosis (195 [9·5%] of 2059 in the intervention group vs 186 [9·1%] of 2051 in the control group; median age 37 years [IQR 30 to 45], 257 [67·5%] male, 124 [32·5%] female). At study closure, primary outcome data were available for 128 (65·6%) of 195 participants in the intervention group and 139 (74·7%) of 186 participants in the control group. 105 (82·0%) of 128 participants in the intervention group and 93 (66·9%) of 139 participants in the control group had a successful patient outcome; 23 (18·0%) of 128 participants in the intervention group and 46 (33·1%) of 139 participants in the control group had an unsuccessful patient outcome. The weighted regression analysis showed a substantial reduction in the risk of unsuccessful patient outcomes in the intervention group compared with the control group (weighted prevalence 15·9% vs 28·6%; RR in weighted population 0·52, 95% CI 0·33 to 0·82; risk difference in weighted population -14·1 percentage points, 95% CI -23·3 to -4·8). Pretreatment loss to follow-up was lower in the intervention group than in the control group (unweighted population: five [3·9%] of 128 participants vs 22 [15·8%] of 139 participants; risk difference in weighted population -9·6 percentage points, 95% CI -14·9 to -4·2).

INTERPRETATION: The package of interventions consisting of pre-test and post-test tuberculosis counselling with conditional cash transfers significantly reduced the risk of unsuccessful tuberculosis patient outcomes, bringing one of the 90-90-90 targets within reach (ie, achieving 90% tuberculosis treatment success). Furthermore, reduction in pretreatment loss to follow-up is expected to reduce transmission and lower incidence of the disease over time.

PMID: 39923785 [Indexed for MEDLINE]

16. NPJ Digit Med. 2025 Jul 3;8(1):399. doi: 10.1038/s41746-025-01812-x.

Effectiveness of symptom monitoring on electronic patient-reported outcomes (ePROs) among patients with lung cancer: a systematic review and meta-analysis.

Symptom monitoring using electronic patient-reported outcomes (ePROs) has demonstrated benefits for patients with cancer, yet the systematic effects for lung cancer remains unknown. This study performed a literature search in Medline, Embase, Cochrane library, CINAHL and APA PsyInfo before April 23rd, 2025, and identified 5755 papers. 18 (0.31%) papers from 11 studies conducting symptom monitoring on ePROs and sending alerts of severe symptoms were included. The meta-analysis showed significant improvement in health-related quality of life (SMD = 2.44, P < 0.001) among patients with lung cancer, with an intervention duration of less than 6 months, 6 months and more than 6 months. When excluding studies that sent alerts to patients themselves, overall survival for lung cancer patients was significantly prolonged (HR = 0.54, 95% CI [0.22, 1.31], P = 0.031). Symptom burden, physical functioning, and healthcare service utilization was also advantaged, but implementation process and cost-effectiveness data was insufficient (Trial registration: CRD420251000397).

PMID: 40604235

17. Lancet Microbe. 2025 Jul 14:101153. doi: 10.1016/j.lanmic.2025.101153. Online ahead of print.

Blood RNA biomarkers and C-reactive protein for triage of adult patients with tuberculosis lymphadenitis and pericarditis in South Africa: a single-centre, prospective, observational, diagnostic accuracy study.

BACKGROUND: Data on the diagnostic accuracy of blood RNA biomarker signatures for extrapulmonary tuberculosis are scarce. We aimed to address this question among people investigated for tuberculosis lymphadenitis and tuberculosis pericarditis.

METHODS: This prospective, observational, diagnostic accuracy study was done at a tertiary hospital in Cape Town, South Africa. We enrolled consecutive symptomatic adults (aged 18 years or older) with presumptive tuberculosis lymphadenitis (Jan 25, 2017, to Oct 9, 2019) or tuberculosis pericarditis (Nov 24, 2016, to Oct 28, 2019). We used microbiological testing of samples from the site of disease as the reference standard. We evaluated the diagnostic accuracy of seven previously reported blood RNA signatures by area under the receiver operating characteristic curve (AUROC) and sensitivity and specificity at prespecified thresholds using two SDs above the mean of a healthy reference control group, benchmarked against blood C-reactive protein and WHO target product profile for a tuberculosis triage test. Decision curve analysis was used to evaluate clinical utility of the best-performing blood RNA signature and C-reactive protein.

FINDINGS: The pooled cohort included 440 individuals, 374 of whom (275 with lymphadenitis and 99 with pericarditis) had at least one microbiological test from the site of disease, blood C-reactive protein, and RNA measurements available and were included in the analysis. 181 (48%) participants were female and 193 (52%) were male. The diagnostic accuracy of blood RNA signatures was similar across patients with lymphadenitis and pericarditis. In pooled analysis of both cohorts, all RNA signatures had similar discrimination, with AUROC point estimates ranging from 0·77 (95% CI 0·72-0·82) to 0·82 (0·77-0·86), and greater than that of C-reactive protein (0·61 [0·56-0·67]). The best-performing signature (Roe3) did not meet the WHO target product profile benchmark for a triage test. At the prespecified threshold, Roe3 had 78% (95% CI 72-83) sensitivity and 69% (62-75) specificity; C-reactive protein at a threshold of 10

mg/L had 83% (77-87) sensitivity and 35% (29-43) specificity. In this setting, decision curve analysis showed that Roe3 offered greater net benefit than other approaches for services aiming to reduce the number needed to investigate with confirmatory testing to fewer than four to identify each individual with tuberculosis.

INTERPRETATION: Our results suggest RNA biomarkers show better accuracy and clinical utility than C-reactive protein to trigger confirmatory tuberculosis testing in patients with tuberculosis lymphadenitis and tuberculosis pericarditis, but still fall short of the WHO target product profile for tuberculosis triage tests.

PMID: 40675164

18. J Thorac Oncol. 2025 Jul 26: S1556-0864(25)00974-8. doi: 10.1016/ j.jtho. 2025.07. 122. Online ahead of print.

Brief Report: Comprehensive Genomic Profiling of Rare Lung Tumors: Adenosquamous Carcinoma and Pulmonary Carcinosarcoma.

In 2025, lung cancer remains the leading cause of cancer-related mortality in both men and women. While the advent of immunotherapy and targeted therapies have revolutionized the treatment of non-small cell lung cancer (NSCLC), treatments for rare histologies such as adenosquamous carcinoma (ASC) and pulmonary carcinosarcoma (PC) remain limited due to insufficient data on molecular profiling. As such, knowledge on the molecular characteristics of rare tumors to inform treatment modalities for targeted approaches is desperately needed. In collaboration with Caris Life Sciences, we present new molecular profiling data including genomic, transcriptomic, and the current landscape of surrogate biomarkers to predict response to immunotherapy for ASC and PC to aid in expansion of knowledge for these rare tumors and expedition of novel therapies.

PMID: 40721085

19. Lancet Respir Med. 2025 Jul 3: S2213-2600(25)00164-X. doi: 10.1016/S2213-2600(25)00164-X. Online ahead of print.

Evidence required to evaluate the use of bacteriologically confirmed asymptomatic tuberculosis disease as a primary endpoint in prevention of tuberculosis disease vaccine licensure trials.

Current licensure trials of new vaccines to prevent tuberculosis disease use bacteriologically confirmed symptomatic tuberculosis disease as the primary endpoint. Globally, the incidence of symptomatic tuberculosis disease is low, making licensure trials large, long, and expensive. New data suggest that bacteriologically confirmed asymptomatic tuberculosis disease might occur more frequently than symptomatic tuberculosis disease. Therefore, if vaccines have efficacy against asymptomatic disease, tuberculosis vaccine licensure trials could include it in the primary endpoint, potentially leading to smaller or shorter trials. We describe the potential benefits and risks of this inclusion in the primary endpoint of tuberculosis vaccine licensure trials. We also simulate licensure trial endpoint accrual and summarise feedback from anonymous regulators and policy makers on the knowledge needed to consider this proposal and research studies needed to fill these evidence gaps. If bacteriologically confirmed asymptomatic tuberculosis disease could be included in the primary endpoint of tuberculosis disease licensure trials, it could lead to cheaper and more rapid tuberculosis vaccine development.

PMID: 40618773

20. ACS Nano. 2025 Jul 22;19(28):25697-25709. doi: 10.1021/acsnano.5c02822. Epub 2025 Jul 11.

Machine Learning-Assisted Multimodal Early Screening of Lung Cancer Based on a Multiplexed Laser-Induced Graphene Immunosensor.

Lung cancer remains the leading cause of cancer-related mortality worldwide, largely due to late-stage diagnosis. Early detection is critical for improving patient outcomes, yet current screening methods, such as low-dose computed tomography (CT), often lack the sensitivity and specificity required for early-stage detection. Here, we present a multimodal early screening platform that integrates a multiplexed laser-induced graphene (LIG) immunosensor with machine learning to enhance the accuracy of lung cancer diagnosis. Our platform enables the rapid, cost-effective, and simultaneous detection of four tumor markers─neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), p53, and SOX2─with limits of detection (LOD) as low as 1.62 pg/mL. By combining proteomic data from the immunosensor with deep learning-based CT imaging features and clinical data, we developed a multimodal predictive model that achieves an area under the curve (AUC) of 0.936, significantly outperforming single-modality approaches. This platform offers a transformative solution for early lung cancer screening, particularly in resource-limited settings, and provides potential technical support for precision medicine in oncology.

PMID: 40644803 [Indexed for MEDLINE]

21. Lancet Glob Health. 2025 Jul 11: S2214-109X(25)00232-3. doi: 10.1016/S2214-109X(25)00232-3. Online ahead of print.

The potential impact of reductions in international donor funding on tuberculosis in low-income and middle-income countries: a modelling study.

Update of

    medRxiv. 2025 Apr 25:2025.04.23.25326313. doi: 10.1101/2025.04.23.25326313.

BACKGROUND: Tuberculosis programmes in many settings rely heavily on international donor funding. In 2025, the United States Agency for International Development (USAID) was dismantled, and other countries announced cuts to overseas development assistance. We quantified the potential epidemiological impacts on the tuberculosis burden attributable to these reductions in funding.

METHODS: We calibrated a deterministic tuberculosis model of Mycobacterium tuberculosis transmission, progression, and care to epidemiological indicators in selected low-income and middle-income countries. Calibration was done with the history matching with emulation method, implemented with the hmer package in R and the Approximate Bayesian computation Markov Chain Monte Carlo method. We projected three future scenarios with the following assumptions: that levels of funding in 2024 would continue, that USAID funding would be terminated from 2025, and that additional reductions in funding through The Global Fund to Fight AIDS, Tuberculosis and Malaria would occur (alongside termination of funding from USAID) in line with current donor announcements from 2025. We assumed a reduction in tuberculosis treatment initiation rates proportional to budget reductions for each scenario, estimating cumulative excess episodes of symptomatic tuberculosis and tuberculosis deaths for each scenario.

FINDINGS: We modelled 79 countries, representing 91% of global tuberculosis incidence and 90% of global tuberculosis mortality in 2023. Our modelling suggested that termination of USAID funding might lead to 1·4 million (95% uncertainty interval 1·1-1·7) excess tuberculosis episodes and 537 700 (451 900-662 300) excess deaths by 2035. Further reductions in funding in line with current announcements by the USA, France, the UK, and Germany could lead to 2·8 million (2·1-3·7), 257 600 (192 500-332 900), 206 000 (153 900-266 100), and 124 700 (93 200-161 000), additional episodes, respectively, of symptomatic tuberculosis and 1·0 million (0·8-1·3), 90 500 (72 400-112 800), 72 400 (57 900-90 100), and 43 800 (35 000-54 500) additional tuberculosis deaths, respectively, in the same period, relative to the scenario of termination of USAID funding.

INTERPRETATION: We estimate substantial potential impacts on tuberculosis morbidity and mortality due to reductions in international donor funding. Expanded support from domestic and international donors is essential to address immediate gaps in services for prevention, diagnosis, and treatment.

PMID: 40659023

22. Lancet Infect Dis. 2025 Jul;25(7):751-763. doi: 10.1016/S1473-3099(24)00814-4. Epub 2025 Mar 5.

Immunogenicity, safety, and efficacy of the vaccine H56:IC31 in reducing the rate of tuberculosis disease recurrence in HIV-negative adults successfully treated for drug-susceptible pulmonary tuberculosis: a double-blind, randomised, placebo-controlled, phase 2b trial.

BACKGROUND: People with tuberculosis who complete treatment remain at risk of recurrent disease. The vaccine H56:IC31 has been shown to be safe and immunogenic in phase 1 and 2 studies, but whether it can reduce the risk of tuberculosis recurrence is unknown.

METHODS: In a double-blind, randomised, placebo-controlled, phase 2b trial in South Africa (five clinical trial sites) and Tanzania (one clinical trial site), we enrolled participants aged 18-60 years, without HIV, who had completed more than 5 months (22 weeks) of treatment for drug-susceptible pulmonary tuberculosis. During trial screening (≤7 days after starting treatment), two sputum samples were obtained and frozen for later comparison to recurrent isolates by whole-genome sequencing (WGS). Eligible participants were randomly assigned (1:1; block size of four) to receive two intramuscular doses in the deltoid, 56 days apart, of H56:IC31 or placebo. After the first dose of H56:IC31 or placebo, participants were followed up until study day 421 (1 year after the second dose) and checked at each visit for tuberculosis signs and symptoms. If

tuberculosis was suspected, two sputum samples were obtained: one sample was tested by automated molecular test (Xpert MTB/RIF Ultra) and sent for liquid culture; and the other sample was stored frozen for later analysis by whole-genome sequencing (WGS). At the last visit (day 421), two sputum samples were obtained from all sputum-productive participants, regardless of symptoms, to detect cases of asymptomatic tuberculosis. The primary endpoint was culture-confirmed recurrent pulmonary tuberculosis (due to relapse with the same strain, reinfection by a different strain, or indeterminate) occuring during the period starting at day 70 (14 days after the second dose) and ending on day 421 (1 year after the second dose). Vaccine efficacy against recurrent tuberculosis was derived from Cox proportional hazards models. Secondary endpoints included vaccine efficacy to prevent tuberculosis relapse or reinfection independently, as differentiated by WGS, and safety and immunogenicity outcomes (H56-specific CD4 T-cell responses and humoral anti-H56 IgG responses). Primary analysis of vaccine efficacy was based on modified intention-to-treat (mITT), in all randomly assigned participants except those with tuberculosis disease recurrence or who withdrew before day 70 (or 14 days after the second dose for those who received both doses). Safety was assessed in all randomly assigned participants who received at least one dose of vaccine or placebo. The trial was registered with ClinicalTrials.gov, NCT03512249, and is complete.

FINDINGS: 831 participants (mean age 34·7 years [SD 11·1]; 229 [28%] female and 602 [72%] male; 549 [66%] Black) were enrolled from Jan 31, 2019, to Jan 20, 2022; 415 participants were randomly assigned to receive H56:IC31 and 416 to receive placebo. Follow-up was completed by March 20, 2023 (mean follow-up duration 410·1 days [SD 82·8]). In the primary mITT analysis, recurrent tuberculosis occurred in 23 of 400 participants in the H56:IC31 group (12 relapses, eight reinfections, and three indeterminate); and in 14 of 406 in the placebo group (six relapses, seven reinfections, and one indeterminate). Vaccine efficacy for prevention of recurrence was -73·8% (95% CI -246·9 to 9·8; p=0·10). Vaccine efficacy for prevention of relapse was -116·1% (-522·2 to 16·3; p=0·11) and for prevention of reinfection was -21·1% (-245·3 to 56·5; p=0·71). 2 weeks after the planned second dose, H56:IC31 had significantly increased the frequencies of H56-specific CD4 T cells expressing interferon-γ, tumour necrosis

factor, interleukin (IL)-2, or IL-17 in vaccinees (median percentage of CD4 T cells, 0·35% [IQR 0·19 to 0·57]) compared with placebo (0·11% [0·09 to 0·23]; p<0·0001). H56-specific IgG responses were significantly higher in H56:IC31 recipients (median arbitrary units per mL, 6·84 [IQR 1·64 to 32·8]) than in placebo recipients (1·94 [1·05 to 3·86]; p<0·0001). A greater proportion of H56:IC31 recipients had mild-to-moderate injection site reactions than placebo recipients (165 [40%] of 415 vs 78 [19%] of 416). No treatment-related serious adverse events were reported. Two participants who received H56:IC31 and six who received placebo died.

INTERPRETATION: Vaccination with H56:IC31 at treatment completion for pulmonary tuberculosis did not reduce the risk of recurrent disease. H56:IC31 was well tolerated and immunogenic but might have increased the risk of relapses by endogenous strains.

PMID: 40056922 [Indexed for MEDLINE]

23. Lancet Microbe. 2025 Jul;6(7):101085. doi: 10.1016/j.lanmic.2025.101085. Epub 2025 Apr 4.

Performance of stool Xpert MTB/RIF Ultra for detection of Mycobacterium tuberculosis among adults living with HIV: a multicentre, prospective diagnostic study.

BACKGROUND: When people living with HIV develop pulmonary tuberculosis, it oftenmanifests without detectable acid-fast bacilli on sputum microscopy. We aimed to assess the diagnostic accuracy of stool Xpert MTB/RIF Ultra (hereafter, Ultra) for Mycobacterium tuberculosis detection among adults with HIV.

METHODS: This multicentre, prospective diagnostic accuracy study was done in outpatient and inpatient health centres in Eswatini, Mozambique, and Uganda. We enrolled adults aged 15 years and older with HIV with presumptive tuberculosis. We evaluated the diagnostic accuracy of stool Ultra using the simple one-step processing method against a composite microbiological reference standard (CMRS) including three WHO-recommended tuberculosis diagnostic tests (urine tuberculosis biomarker-based lateral-flow lipoarabinomannan [TB-LAM], sputum Ultra, and sputum culture), and stratified by CD4 cell count. We compared sputum versus stool Ultra performance against a composite reference standard of TB-LAM and sputum culture (CMRS2). We also calculated the diagnostic yield among all tested. This study is registered with ClinicalTrials.gov, NCT05047315.

FINDINGS: Between Dec 2, 2021, and Aug 14, 2024, 677 participants were enrolled (247 [36%] men and 430 [64%] women). Tuberculosis was microbiologically confirmed in 119 participants by the CMRS: 39 (33%) had a positive test with sputum Ultra, 30 (25%) had a positive test with culture, and 84 (71%) had a positive test with urine TB-LAM. The sensitivity of stool Ultra compared with CMRS was 23·7% (28/118 [95% CI 16·4-32·4]) and the specificity was 94·0% (504/536 [91·7-95·9]). The sensitivity of stool Ultra in participants with CD4 counts less than or equal to 200 cells per μL was 45·5% (10/22 [24·4-67·8]) compared with 21·3% (17/80 [12·9-31·8]) in those with CD4 counts greater than 200 cells per μL. Against the CMRS2, we observed no differences in sensitivity between sputum and stool Ultra on the basis of CD4 cell count. Stool Ultra resulted in additional cases detected of 23% (30/133) compared with sputum Ultra, 29% (38/133) compared with sputum culture, and 33% (44/133) compared with TB-LAM. The overall diagnostic yield for all treated for stool Ultra was 9% (60/677), for TB-LAM was 12% (84/677), for sputum Ultra was 6% (39/677), and for sputum culture was 4% (30/677).

INTERPRETATION: These results suggest stool Ultra could be used as an additional test for tuberculosis diagnosis among people with HIV, particularly among those with CD4 counts less than 200 cells per μL.

PMID: 40194533 [Indexed for MEDLINE]

24. Nat Commun. 2025 Jul 11;16(1):6442. doi: 10.1038/s41467-025-61703-3.

Trehalose catalytic shift inherently enhances phenotypic heterogeneity and multidrug resistance in Mycobacterium tuberculosis.

Update of

    Res Sq. 2024 Sep 13:rs.3.rs-4999164. doi: 10.21203/rs.3.rs-4999164/v1.

Drug-resistance (DR) in bacteria often develops through the repetitive formation of drug-tolerant persisters, which survive antibiotics without genetic changes. It is unclear whether Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), undergoes a similar transitioning process. Recent studies highlight changes in trehalose metabolism as crucial for persister formation and drug resistance. Here, we observe that mutants lacking trehalose catalytic shift activity exhibited fewer DR mutants due to decreased persisters. This shift enhances Mtb survival during antibiotic treatment by increasing metabolic heterogeneity and drug tolerance, facilitating drug resistance. Rifampicin (RIF)-resistant bacilli display cross-resistance to other antibiotics linked to higher trehalose catalytic shift, explaining how multidrug resistance (MDR) can follow RIF-resistance. In particular, the HN878 W-Beijing strain exhibits higher trehalose catalytic shift, increasing MDR risk. Both genetic and pharmacological inactivation of this shift reduces persister formation and MDR development, suggesting trehalose catalytic shift as a potential therapeutic target to combat TB resistance.

PMID: 40645928 [Indexed for MEDLINE]

25. Cancer Cell. 2025 Jul 1: S1535-6108(25)00262-4. doi: 10.1016/j.ccell.2025.06.012. Online ahead of print.

Subclonal immune evasion in non-small cell lung cancer.

Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.

PMID: 40614739

26. Cell Host Microbe. 2025 Jul 9;33(7):1089-1105.e7. doi: 10.1016/j.chom.2025.06.013.

Lactate production by tumor-resident Staphylococcus promotes metastatic colonization in lung adenocarcinoma.

The role of the lung microbiota in cancer remains unclear. Here, we reveal that Staphylococcus is selectively enriched in metastatic tumor lesions and is associated with tumor recurrence in lung cancer patients. Using patient-derived bacterial strains, we employ a combination of cell line, organoid, mouse allograft, and xenograft models to demonstrate that S. nepalensis and S. capitis promote the metastatic potential of lung cancer cells. Mechanistically, lactate secreted by S. nepalensis and S. capitis upregulates MCT1 expression in tumor cells, facilitating lactate uptake and activating pseudohypoxia signaling. These effects can be eliminated by knocking out the lactate-producing genes (D-lactate dehydrogenase [ddh]/L-lactate dehydrogenase [ldh]) in the bacterial strains. Furthermore, we show that inhibiting MCT1 attenuates Staphylococcus-induced tumor metastasis both in vitro and in vivo. Collectively, our results demonstrate that tumor-resident Staphylococcus species promote lung cancer metastasis by activating host pseudohypoxia signaling and further identify key regulators as potential targets for therapeutic development.

PMID: 40639336 [Indexed for MEDLINE]

27. Am J Respir Crit Care Med. 2025 Jul;211(7):1241-1252. doi: 10.1164/rccm.202409-1738OC.

Carcinogenic Industrial Air Emissions and Lung Cancer Risk in a Cohort of 440,000 Americans.

Comment in

    Am J Respir Crit Care Med. 2025 Jul;211(7):1120-1122. doi: 10.1164/rccm.202504-0966ED.

Rationale: Industrial facilities emit known lung carcinogens into air, but the association of these agents with lung cancer risk at environmental levels is unknown. Objectives: We sought to investigate industrial emissions and lung cancer risk. Methods: We used a U.S. regulatory database to estimate airborne exposure to known and probable human carcinogens (n = 31) emitted from industrial sources (1987-1995) for 442,986 participants in the NIH-AARP Diet and Health Study. We estimated inverse distance- and wind-weighted average exposures within 1, 2, 5, and 10 km of the enrollment residence. Using Cox proportional hazards models adjusted for smoking and other confounders, we evaluated lung cancer risk overall and by major histologic subtype (adenocarcinoma, squamous cell carcinoma, small cell carcinoma) for levels (tertiles and medians) of exposure to each agent. Measurements and Main Results: Among agents with prior evidence of lung carcinogenicity, overall risk was elevated for cobalt (5-km hazard ratio (HR) for tertile3 (T3) = 1.19; 95% confidence interval [CI] = 1.10-1.29; p-trend ⩽ 0.0001; 10-km HRT3 = 1.15; 95% CI = 1.09-1.21; p-trend ⩽ 0.0001) and beryllium (5-km HRT3 = 1.20; 95% CI = 0.94-1.55; p-trend = 0.15; 10-km HRT3 = 1.15; 95% CI = 1.01-1.31; p-trend = 0.02). We also observed associations with benzene and nickel. For agents without prior evidence, styrene was associated with risk at 1 km (HRT3 = 1.22; 95% CI = 1.00-1.48; p-trend = 0.03). Diethyl sulfate, chromium, and lead were also associated with risk. Associations for cobalt, benzene, nickel, and diethyl sulfate were most apparent for squamous cell carcinoma. Conclusions: Our novel findings show that relatively high air emissions of numerous carcinogenic industrial agents near the home were associated with lung cancer risk unexplained by smoking. These and the stronger associations for squamous cell carcinoma highlight the potential role of industrial exposures in lung cancer development.

PMID: 40315142 [Indexed for MEDLINE]

28. Nature. 2025 Aug;644(8075):133-144. doi: 10.1038/s41586-025-09219-0. Epub 2025 Jul 2.

The mutagenic forces shaping the genomes of lung cancer in never smokers.

Lung cancer in never smokers (LCINS) accounts for around 25% of all lung cancers1,2 and has been associated with exposure to second-hand tobacco smoke and air pollution in observational studies3-5. Here we use data from the Sherlock-Lung study to evaluate mutagenic exposures in LCINS by examining the cancer genomes of 871 treatment-naive individuals with lung cancer who had never smoked, from 28 geographical locations. KRAS mutations were 3.8 times more common in adenocarcinomas of never smokers from North America and Europe than in those from East Asia, whereas a higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas of never smokers from East Asia. Signature SBS40a, with unknown cause6, contributed the largest proportion of single base substitutions in adenocarcinomas, and was enriched in cases with EGFR mutations. Signature SBS22a, which is associated with exposure to aristolochic acid7,8, was observed almost exclusively in patients from Taiwan. Exposure to secondhand smoke was not associated with individual driver mutations or mutational signatures. By contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations and shorter telomeres. They also exhibited an increase in most types of mutations, including a 3.9-fold increase in signature SBS4, which has previously been linked with tobacco smoking9, and a 76% increase in the clock-like10 signature SBS5. A positive dose-response effect was observed with air-pollution levels, correlating with both a decrease in telomere length and an increase in somatic mutations, mainly attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

PMID: 40604281 [Indexed for MEDLINE]

29. Cancer Cell. 2025 Jul 5: S1535-6108(25)00261-2. doi: 10.1016/j.ccell.2025.06.011. Online ahead of print.

KEAP1 and STK11/LKB1 alterations enhance vulnerability to ATR inhibition in KRAS mutant non-small cell lung cancer.

KRAS mutations frequently co-occur with alterations in STK11/LKB1 and/or KEAP1, defining an aggressive subset of lung cancers resistant to immuno- and chemotherapy. While LKB1 loss is associated with vulnerability to DNA damage response-based therapies, the impact of KEAP1 alterations remains unknown. We demonstrate that KEAP1-NRF2 pathway drives a compensatory modulation of ATR-CHK1 signaling, enhancing vulnerability to ATR inhibitors (ATRi), particularly in the setting of increased replication stress associated with LKB1 loss. ATRi shows enhanced anti-tumor activity in LKB1 and/or KEAP1-deficient non-small cell lung cancer (NSCLC) models and synergizes with gemcitabine. ATRi also enhances antitumor immunity and mitigates the immunosuppressed phenotype of LKB1/KEAP1-deficient tumors. In the HUDSON trial, LKB1/KEAP1-deficient NSCLC patients demonstrate enhanced benefits to the ATRi ceralasertib plus durvalumab. These findings suggest that alterations in the KEAP1-NRF2 pathway and/or LKB1 are associated with enhanced sensitivity to ATRi and could serve as biomarkers for predicting response to ATRi combination regimens.

PMID: 40645185

30. N Engl J Med. 2025 Jul 24;393(4):349-361. doi: 10.1056/NEJMoa2502099. Epub 2025 Jun 2.

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy.

BACKGROUND: Tarlatamab, a bispecific delta-like ligand 3-directed T-cell engager immunotherapy, received accelerated approval for the treatment of patients with previously treated small-cell lung cancer. Whether tarlatamab is more effective than chemotherapy in the treatment of patients whose small-cell lung cancer has progressed during or after initial platinum-based chemotherapy is not known.

METHODS: We conducted a multinational, phase 3, open-label trial to compare tarlatamab with chemotherapy as second-line treatment in patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. Patients were randomly assigned to receive tarlatamab or chemotherapy (topotecan, lurbinectedin, or amrubicin). The primary end point was overall survival. Key secondary end points were investigator-assessed progression-free survival and patient-reported outcomes. Results of the prespecified interim analysis (data-cutoff date, January 29, 2025) are reported.

RESULTS: A total of 509 patients were randomly assigned to receive tarlatamab (254 patients) or chemotherapy (255 patients). Treatment with tarlatamab resulted in significantly longer overall survival than chemotherapy (median, 13.6 months [95% confidence interval {CI}, 11.1 to not reached] vs. 8.3 months [95% CI, 7.0 to 10.2]; stratified hazard ratio for death, 0.60; 95% CI, 0.47 to 0.77; P<0.001). Tarlatamab treatment also had a significant benefit with respect to progression-free survival and cancer-related dyspnea and cough as compared with chemotherapy. The incidence of adverse events of grade 3 or higher was lower with tarlatamab than with chemotherapy (54% vs. 80%), as was the incidence of adverse events resulting in treatment discontinuation (5% vs. 12%).

CONCLUSIONS: Treatment with tarlatamab led to longer overall survival than chemotherapy among patients with small-cell lung cancer whose disease had progressed during or after platinum-based chemotherapy. (Funded by Amgen; DeLLphi-304 ClinicalTrials.gov number, NCT05740566.).

PMID: 40454646 [Indexed for MEDLINE]

31. J Thorac Oncol. 2025 Jul;20(7):856-870. doi: 10.1016/j.jtho.2025.01.013. Epub 2025 Jan 24.

The International Association for the Study of Lung Cancer Staging Project: The Database and Proposal for the Revision of the Staging of Pulmonary Neuroendocrine Carcinoma in the Forthcoming Ninth Edition of the TNM Classification for Lung Cancer.

INTRODUCTION: Pulmonary high-grade neuroendocrine carcinoma (NEC) includes SCLC and large cell NEC (LCNEC). The seventh and eighth editions of the TNM classification for lung cancer confirmed the applicability of this staging system for SCLC. With the proposal of N2 and M1c subcategories for the ninth edition classification, we assessed the applicability to NECs.

METHODS: The database included NEC cases diagnosed between January 2011 and December 2019. Eligible cases, with valid survival time and eighth edition TNM stage, were classified as pure SCLC, combined SCLC with NSCLC, and LCNEC. Survival was calculated using the Kaplan-Meier method, pairwise differences using a log-rank test, and prognostic groups using a Cox regression analysis.

RESULTS: There were 6181 pure and combined SCLC and 697 LCNEC cases available. For SCLC, survival outcome analyses included 4453 cases with clinical stage and 583 with pathologic stage data. The corresponding numbers for LCNEC were 585 and 508. The SCLC data validated the ninth edition classification for lung cancer, including the proposed new subcategories, N2a, single-station ipsilateral mediastinal or subcarinal lymph node involvement, and N2b, involvement of multiple ipsilateral or subcarinal stations. The data also validated the subcategorization of M1c into M1c1 (multiple lesions in a single extrathoracic organ system) and M1c2 (involvement of multiple extrathoracic organ systems). The LCNEC data were insufficient for complete survival analysis, but the available data reported decreasing survival with increasing clinical and pathologic stages.

CONCLUSIONS: The ninth edition TNM classification applies to patients with NEC and is the appropriate standard for use in clinical practice.

PMID: 39864546 [Indexed for MEDLINE]

32. J Thorac Oncol. 2025 Jul 22: S1556-0864(25)00937-2. doi: 10.1016/ j.jtho.2025.07. 114. Online ahead of print.

The 2024 International Association for the Study of Lung Cancer (IASLC) Global Survey on Biomarker Testing.

INTRODUCTION: Biomarker status is vital to inform optimal care for individuals with lung cancer, yet implementation of testing has been sub-optimal due to cost, lack of quality and standards, access, awareness, and long turnaround times. Recent therapeutic advances in late-stage and early-stage lung cancer motivated a second global survey on comprehensive biomarker testing in 2024.

METHODS: The IASLC convened a global multidisciplinary committee to develop the survey. We used a mixed methods framework, with qualitative focus groups and in-depth interviews informing the primarily quantitative survey. The survey was available in 6 languages.

RESULTS: We received 1,677 responses across 90 countries and 14 disciplines. Respondents believe biomarker testing significantly impacts outcomes (98.3%) and have a clear understanding of who should receive testing (91.2%). However, only 63.4% and 29.4% ranked it highly important to perform comprehensive biomarker testing in late- and early-stage, respectively. Many respondents (67%) estimated more than half of individuals with lung cancer are biomarker tested in their country, up from 39% in the 2018 survey (p-value<0.0001). However, 43% of respondents sometimes/often treat patients prior to receiving biomarker results. The highest ranked barriers were cost (27.2%), time (13.9%), sample quality (13.8%), access (12.8%), and awareness (8.0%). We found that healthcare system support for biomarker testing varied by country-level income.

CONCLUSIONS: We found improvements in the perception of testing rates compared to 2018 but continued and substantial barriers exist. Future initiatives will use these data to target awareness, access, processes, and policy initiatives to improve comprehensive testing globally.

PMID: 40706709