PubMed：

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

Filters applied: from 2026/07/01 - 2026/07/31.

1. Cell. 2026 Jul 9;189(14):4276-4294.e33. doi: 10.1016/j.cell.2026.04.038.

Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.

Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13+ fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.

PMID: 42161272 [Indexed for MEDLINE]

2. N Engl J Med. 2026 Jul 9;395(2):151-161. doi: 10.1056/NEJMoa2518990.

Ensartinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Anaplastic lymphoma kinase (ALK) inhibitors have emerged as promising agents for patients with resectable ALK-positive non-small-cell lung cancer (NSCLC). Whether ensartinib, a second-generation ALK inhibitor, is safe and effective in such patients is unknown.

METHODS: In this phase 3, double-blind, randomized trial involving patients with completely resected, ALK-positive stage IB to IIIB NSCLC after adjuvant chemotherapy, we randomly assigned patients in a 1:1 ratio to receive ensartinib at a dose of 225 mg once daily or placebo for 24 months. The primary end point was disease-free survival in patients with stage II to IIIB NSCLC. The key secondary end point was disease-free survival in the overall patient population.

RESULTS: A total of 274 patients were randomly assigned to receive ensartinib or placebo (137 patients in each group). At 24 months, the percentage of patients with stage II to IIIB disease who were alive and disease-free was 86.4% in the ensartinib group and 53.5% in the placebo group (hazard ratio for disease recurrence or death, 0.20; 95% confidence interval [CI], 0.11 to 0.38; P<0.001). In the overall patient population, the percentage of patients who were alive and disease-free was 87.3% in the ensartinib group and 57.2% in the placebo group (hazard ratio, 0.20; 95% CI, 0.10 to 0.37; P<0.001). Overall survival data were immature. Adverse events of grade 3 or higher occurred in 35.8% of the patients who received ensartinib (most commonly rash) and in 18.2% of those who received placebo.

CONCLUSIONS: Among patients with completely resected stage IB to IIIB ALK-positive NSCLC, the percentage of patients who were alive and disease-free at 24 months was significantly higher with ensartinib than with placebo. (Funded by Betta Pharmaceuticals; ELEVATE ClinicalTrials.gov number, NCT05341583.).

PMID: 42418775 [Indexed for MEDLINE]

3. JAMA. 2026 Jul 28;336(4):323-333. doi: 10.1001/jama.2026.8044.

Biomarker-Based Eligibility for Lung Cancer Screening: Validation of the Protein-Based INTEGRAL-Risk Model.

IMPORTANCE: Screening by low-dose computed tomography can reduce lung cancer mortality among high-risk individuals, but many lung cancers occur among individuals with a smoking history who are not eligible for screening.OBJECTIVE: To develop and validate the protein-based Integrative Analysis of Lung Cancer Risk and Etiology (INTEGRAL)-Risk model in individuals with a smoking history from the general population.

DESIGN, SETTING, AND PARTICIPANTS: Cohorts in the Lung Cancer Cohort Consortium recruited research participants in the US, Europe, Asia, and Australia between 1985 and 2009, who were followed up for lung cancer and other health outcomes until 2021. Fourteen case cohorts of 3695 participants with a smoking history within the Lung Cancer Cohort Consortium, including 2305 randomly sampled participants and 1390 patients diagnosed with lung cancer within 3 years after blood sample collection, were designed. Plasma or serum samples from each participant were assayed using the INTEGRAL protein panel in 2022. The INTEGRAL-Risk model was trained using 7 predefined case cohorts (training set; n = 1951) to estimate absolute risk of being diagnosed with lung cancer based on age, smoking history, and 13 proteins. The validity of the INTEGRAL-Risk model was assessed in 7 independent case cohorts (testing set; n = 1744) at 1, 2, and 3 years after blood collection.

EXPOSURE: Absolute risk estimates from the protein-based INTEGRAL-Risk model.

MAIN OUTCOMES AND MEASURES: The primary outcome was the validity of the INTEGRAL-Risk model in the testing set with respect to discrimination (area under the curve [AUC]) and calibration (ratio of expected-to-observed cases [E/O]).

RESULTS: A total of 3695 participants were included, with 1951 participants (including 807 with lung cancer) in the training set and 1744 participants (including 583 with lung cancer) in the testing set. In the combined 14 training and testing sets, after application of statistical weights, 323 570 participants were represented (185 016 [57%] female; median [IQR] age, 60 [51-67] years). In the independent testing set, discrimination of the INTEGRAL-Risk model was highest at 1 year of follow-up and exceeded that of the questionnaire-based PLCOm2012 (Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial) model (INTEGRAL-Risk AUC of 0.88 [95% CI, 0.85-0.91] vs PLCOm2012 AUC of 0.79 [95% CI, 0.75-0.83]; P value for difference <.001). Using a risk threshold to achieve the same specificity as US Preventive Services Task Force (USPSTF) 2021 criteria, the INTEGRAL-Risk model captured 85% of lung cancer cases compared with 63% by USPSTF 2021 and 70% by PLCOm2012. Discrimination of the INTEGRAL-Risk model decreased with longer prediction horizons, with a 2-year AUC of 0.84 (95% CI, 0.81-0.86) and 3-year AUC of 0.81 (95% CI, 0.79-0.83). The model was well calibrated (E/O over 3 years, 0.87 [95% CI, 0.69-1.14]).

CONCLUSIONS AND RELEVANCE: Compared with questionnaire-based approaches, the protein-based INTEGRAL-Risk model improved short-term prediction of lung cancer in people with a smoking history. This model has potential to improve selection of high-risk individuals who are most likely to benefit from lung cancer screening.

PMID: 42149699 [Indexed for MEDLINE]

4. CA Cancer J Clin. 2026 Jul-Aug;76(4):e70090. doi: 10.3322/caac.70090.

Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries.

This article provides updated global cancer statistics for the year 2024 based on the GLOBOCAN estimates of the International Agency for Research on Cancer. The authors describe national cancer incidence and mortality by world region and the Human Development Index and predict the burden in 2050 based on demographic trends. In 2024, an estimated 20.6 million new cancer cases (19.5 million excluding nonmelanoma skin cancer) and 9.8 million deaths (9.7 million excluding nonmelanoma skin cancer) occurred worldwide, equivalent to one in five people developing cancer during their lifetime and one in nine men and one in 13 women dying from the disease. Lung cancer is the most frequently diagnosed cancer, responsible for almost 2.6 million new cases (12.8%), followed by female breast (11.8%), colorectal (9.9%), prostate (7.5%), and stomach (4.7%) cancer. Lung cancer is also the leading cause of cancer death, with an estimated 1.9 million deaths (19.1%), followed by colorectal (9.4%), liver (7.5%), female breast (7.1%), and stomach (6.6%) cancer. Incidence rates vary four- to five-fold across regions, with the highest rates found in Australia/New Zealand (men, 477 per 100,000; women, 396 per 100,000), whereas mortality rates differ two-fold, with elevated rates in Eastern Europe for men (158 per 100,000) and Melanesia for women (108 per 100,000). The incidence burden is predicted to reach 34.4 million by 2050, up 67% from 2024, with the largest proportional increases in lower Human Development Index countries. Although global variation in cancer profiles demands a nuanced approach to cancer control at national and regional levels, primary prevention must be at the forefront, including intensified efforts to reduce tobacco use, prevent infections, lower alcohol consumption and excess body weight, and increase physical activity.

PMID: 42417444 [Indexed for MEDLINE]

5. Lancet Infect Dis. 2026 Jul;26(7):e315-e325. doi: 10.1016/S1473-3099(25)00548-1.

Post-tuberculosis lung disease: a case definition for use in research studies.

Despite growing awareness of the substantial burden of long-term pulmonary impairment among tuberculosis survivors, marked variability in how post-tuberculosis lung disease is defined across research studies limits the comparison of findings and synthesis of evidence. To facilitate greater harmonisation within the field, we propose a case definition for post-tuberculosis lung disease for use in research studies. Conceptual aspects of this case definition were initially developed with input from a broad group of stakeholders at the 2nd International Post-Tuberculosis Symposium and were refined by the authors after the Symposium. Guiding principles for the definition include specificity, feasibility in settings with high tuberculosis disease burdens, probable relevance to long-term health outcomes, and applicability across the lifespan. The definition is designed to be used alongside, rather than instead of, study-specific definitions used to explore primary study hypotheses, and is accompanied by a reporting framework. The case definition has three components: that the individual had previous pulmonary or pleural tuberculosis disease and does not have tuberculosis disease at the time of evaluation; that the individual has, at the time of assessment, evidence of pulmonary disease with abnormalities in at least two of three clinical domains of lung function, respiratory symptoms, and chest imaging; and that the pulmonary disease manifestations should be attributable at least in part to previous tuberculosis disease. This definition is developed in the absence of data on long-term patient outcomes and will need to evolve over time in response to emerging evidence. However, we believe this proposed definition will lead to greater consistency and rigor across studies of post-tuberculosis lung disease with the goal of improving care and quality of life for millions of tuberculosis survivors worldwide.

PMID: 41232546 [Indexed for MEDLINE]

6. Lancet Infect Dis. 2026 Jul;26(7):e289-e301. doi: 10.1016/S1473-3099(26)00019-8.

Accelerating research and development of new vaccines against tuberculosis: 5-year progress on the global roadmap.

In 2021, a global tuberculosis vaccine research and development roadmap proposed a series of actions to accelerate the development of new, effective, and affordable vaccines that are urgently needed to eliminate tuberculosis globally. Since then, the pipeline has diversified, several candidates are currently in phase 3 clinical trials, and many low-income and middle-income countries have made important steps in anticipating regulatory approval. However, the number of candidates in active clinical trials is small and product development challenges persist. Engagement with vaccine manufacturers has increased but is hampered by unclear demand and insufficient committed procurement. Investment in tuberculosis vaccine research and development therefore remains risky and inadequate. In parallel, more work is needed to identify and plan for cost-effective implementation while mitigating potential hesitancy and stigma to ensure uptake of new tuberculosis vaccines once licensed. Increased diversification of funders and strategic coordination of multiple stakeholders is needed more than ever.

PMID: 41864213 [Indexed for MEDLINE]

7. Lancet Infect Dis. 2026 Jul 1:S1473-3099(26)00222-7. doi: 10.1016/S1473-3099(26)00222-7. Online ahead of print.

Community-based tuberculosis screening with computer-aided detection technology alone and in combination with point-of-care C-reactive protein testing: a paired screen-positive trial.

BACKGROUND: Active tuberculosis case-finding in communities is crucial for early disease detection and disruption of transmission; however, it is complex and costly. A thorough analysis of tuberculosis screening strategies is essential, particularly because the health systems affected often have limited resources. We aimed to compare two community screening approaches in terms of tuberculosis case yield and cost.

METHODS: This pragmatic community trial, with a paired screen-positive design (ie, within-person comparison), was conducted in the Butha-Buthe District in Lesotho and the uMgungundlovu District in South Africa. All household members aged at least 18 years were eligible to participate, except those who were seriously ill, had a condition that prevented their safe and full participation, were receiving tuberculosis treatment, or were pregnant (Lesotho only). We compared two screening approaches: the use of computer-aided detection (CAD) software on digital chest x-rays alone (the CAD4TBv7 approach) and the use of CAD followed by a C-reactive protein (CRP) test if the CAD score was in a particular range (the CAD4TBv7-CRP approach). A confirmatory Xpert MTB/RIF Ultra test was conducted when required by the algorithm of one or both approaches. Coprimary outcomes were to establish whether the CAD4TBv7-CRP approach was non-inferior to the CAD4TBv7 approach (non-inferiority margin -10%) and to conduct a comparative cost analysis between the two approaches.

FINDINGS: Among 20 023 enrolled participants, the median age was 42 years (IQR 29-60); 12 387 (61·9%) participants were female, 7625 (38·1%) were male, and 11 (0·1%) were intersex. 4534 (22·6%) of 20 023 participants were living with HIV, 1547 (7·7%) had a history of tuberculosis, and 1545 (7·7%) reported at least one of the four main symptoms of tuberculosis. The primary outcome set, defined as participants who were identified as having tuberculosis according to at least one of the two approaches and had complete data for both approaches, comprised 73 participants: the CAD4TBv7 approach identified 69 (94·5%) of these cases of tuberculosis and the CAD4TBv7-CRP approach identified 60 (82·2%) cases. The difference of -12·3% (95% CI -23·0 to -1·6) indicates that the non-inferiority criterion was not met. The cost per detected case of tuberculosis was US$5454 (95% uncertainty interval 4294-6777) for the CAD4TBv7 approach and $7486 (5948-9246) for the CAD4TBv7-CRP approach, making the CAD4TBv7-CRP approach 37·3% more expensive.

INTERPRETATION: In active tuberculosis case-finding in our community setting, the combination of CAD followed by CRP testing offered no advantage over CAD alone owing to its inferior case yield and higher cost. CAD alone, however, has the potential to be an effective and economically viable tuberculosis screening strategy in areas with high disease burden.

PMID: 42385764

8. Lancet Glob Health. 2026 Jul 28:103988. doi: 10.1016/j.langlo.2026.103988.

In-home tongue swab testing for tuberculosis screening among household contacts in South Africa: a prospective cohort study.

BACKGROUND: Household contact investigation for tuberculosis is limited by reliance on clinic-based testing and sputum-dependent diagnostics. To inform household-level screening strategies, we estimated the diagnostic accuracy of in-home molecular testing using tongue swabs compared with sputum, and quantified linkage to care among household contacts with confirmed tuberculosis.

METHODS: We conducted a prospective cohort study at 26 government health clinics in South Africa. We recruited index patients with drug-sensitive pulmonary tuberculosis and their household contacts. Participants aged 18 years or older and not on tuberculosis treatment within the past 6 months were eligible. Household contacts provided tongue swabs and, where possible, sputum specimens during household visits. Xpert MTB/RIF Ultra on GeneXpert Omni or Edge devices were used. Tongue swabs were tested individually or in pools of up to three participants, whereas sputa were tested individually. The primary outcome was the estimated diagnostic accuracy (ie, sensitivity and specificity) of tongue swab testing compared with sputum using paired results, irrespective of pooling strategy. Secondary outcomes included performance of pooled tongue swab testing as a household-level screening strategy (defined by conditional detection of tuberculosis by pool size and the residual probability of underlying tuberculosis following a negative pooled result) and linkage to care (defined as the proportion of individuals with a positive sputum result presenting for clinic-based tuberculosis services and their time-to-clinic presentation).

FINDINGS: Between June 15, 2021, and Oct 29, 2024, 438 households and 909 household contacts were enrolled. The median age of household contacts was 39 years (IQR 28-55), 570 (62·7%) of 909 were female and 338 (37·2%) were male, 377 (41·5%) were symptomatic, 132 (14·5%) reported living with HIV, and 207 (22·8%) had a previous history of tuberculosis. Tongue swabs were obtained from 901 (99·1%) of 909 household contacts, whereas 292 (32·1%) produced sputum. Among 203 paired tongue swab-sputum results, sensitivity of tongue swab testing was 61·9% (95% CI 38·4-81·9) and specificity was 100% (98·9-100). Among individually tested tongue swabs paired with sputum results (58 paired tests), sensitivity was 100% (95% CI 47·8-100) and specificity was 100% (93·3-100). Among pooled tests in which at least one contributing participant was sputum-positive, five (55·6%) of nine for two-swab pools and three (42·9%) of seven for three-swab pools tested positive. Among pooled tests with a negative result, the residual probability of an underlying sputum-positive case was four (4·4%) of 91 for two-swab pools and four (9·5%) of 42 for three-swab pools. Sputum testing identified 29 (3·2%) of 909 household contacts with tuberculosis (all previously undiagnosed). Following referral, 25 (86·2%) of 29 presented for clinic-based care within a median of 1 day (IQR 1-2).

INTERPRETATION: In-home molecular testing using tongue swabs enabled near-universal specimen collection and microbiological testing among household contacts. When implemented as a pooled, household-level screening approach, tongue swab testing identified tuberculosis among contacts unable to produce sputum and reduced the need for universal individual testing. However, pooling was associated with a measurable residual risk of missed disease following negative pooled results. These findings indicate that efficiency gains from pooled tongue swab testing must be balanced against the residual risk of missed cases.

PMID: 42520827

9. JAMA. 2026 Jul 28;336(4):306-314. doi: 10.1001/jama.2026.7745.

Bispecific Antibody Ivonescimab Added to Chemotherapy in EGFR-Variant Non-Small Cell Lung Cancer: The HARMONi-A Randomized Clinical Trial.

IMPORTANCE: Patients with epidermal growth factor receptor (EGFR) gene variant nonsquamous non-small cell lung cancer (NSCLC) who have disease progression after prior EGFR tyrosine kinase inhibitor (TKI) therapy have limited treatment options, creating a need for more effective subsequent therapies.

OBJECTIVE: To provide final overall results of a trial assessing whether adding ivonescimab (a bispecific antibody targeting programmed cell death protein 1 and vascular endothelial growth factor) to chemotherapy improves overall survival in this population.

DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted at 55 sites in China. From January 25 to November 2, 2022, a total of 322 adult patients with locally advanced or metastatic EGFR-variant nonsquamous NSCLC who had received prior EGFR-TKI therapy were enrolled. The data cutoff date was April 12, 2025.INTERVENTIONS: Patients were randomized 1:1 to receive ivonescimab (20 mg/kg; n = 161) or placebo (n = 161) plus chemotherapy with pemetrexed and carboplatin once every 3 weeks for 4 cycles, followed by maintenance therapy.

MAIN OUTCOMES AND MEASURES: This final results report focuses on overall survival, the key secondary end point, tested in a hierarchical manner (the primary end point was progression-free survival assessed by an independent radiology review committee).

RESULTS: The 322 enrolled patients had a median age of 59.4 years, and 51.6% were female. During a median follow-up of 32.5 months, ivonescimab plus chemotherapy improved overall survival compared with chemotherapy alone (median survival, 16.8 months vs 14.1 months; stratified hazard ratio, 0.74; 95% CI, 0.58-0.95; P = .02). The absolute difference in median overall survival was 2.7 months. Estimated 30-month survival rates were 29.1% (95% CI, 22.1%-36.4%) with ivonescimab and 18.4% (95% CI, 12.8%-24.8%) with placebo. Grade 3 or higher treatment-emergent adverse events occurred in 67.1% and 54.7% of patients receiving ivonescimab and placebo, respectively.

CONCLUSIONS AND RELEVANCE: Ivonescimab plus chemotherapy provided a statistically significant and clinically meaningful improvement in overall survival with an acceptable safety profile in patients with EGFR-variant NSCLC after EGFR-TKI therapy.

PMID: 42307937 [Indexed for MEDLINE]

10. JAMA Oncol. 2026 Jul 1;12(7):705-713. doi: 10.1001/jamaoncol.2026.1080.

Rates of Systemic Treatment for Metastatic Non-Small Cell Lung Cancer Among Older Adults.

IMPORTANCE: Metastatic non-small cell lung cancer (mNSCLC) has very high mortality rates, and comprises approximately half of new cases of lung cancer; however, highly effective and better tolerated treatments have become available in recent decades. Nevertheless, population-level treatment of mNSCLC is poorly characterized in the era of rapid treatment advances.

OBJECTIVE: To characterize treatment rates, trends, and factors associated with treatment of mNSCLC.

DESIGN, SETTING, AND PARTICIPANTS: This population-based study used linked Surveillance Epidemiology and End Results (SEER) and Medicare claims data and the analysis included patients 65 years and older diagnosed with mNSCLC from January 2006 to December 2021. Data were analyzed from October 2025 to February 2026.

EXPOSURES: Sociodemographic variables, comorbidity burden, histologic type, referral to subspecialist, enrollment in Medicare Part D, and biomarker testing.

MAIN OUTCOMES: The primary outcome was receipt of systemic treatment. Statistical analyses included summary statistics and a competing risk proportional hazards model for receipt of systemic treatment.

RESULTS: Of 254 611 patients with mNSCLC, the cohort median (IQR) age was 73 (68-80) years, with 133 635 (52.5%) male individuals; a total of 9512 (3.7%) were Asian, 26 546 (10.4%) were Black, 4553 (1.8%) were Hispanic, 205 381 (80.7%) were White, and 8619 (3.4%) were another or unknown race. A total of 119 197 patients (46.8%) ever received systemic treatment. Of the 100 367 (39.8%) who died within 90 days of diagnosis, 13.2% were treated compared with 69% of those surviving more than 90 days. The treated proportion increased only slightly between 2006 and 2021. In a competing risk model, referral to oncology specialists was associated with treatment (hazard ratio [HR], 2.5; 95% CI, 2.41-2.67; P < .001) which corresponded to a 30.3% greater cumulative incidence of treatment at 180 days (CIF180) compared with those without a referral. Similarly, those with biomarker testing had a 17.8% greater CIF180, whereas those older than 80 years had a 15.4% lower CIF180 compared to those aged 65 to 69 years. Patients with NSCLC not otherwise specified histologic findings had a 12.8% lower CIF180 compared with those with adenocarcinoma histologic findings. Other factors associated with significant but smaller differences in receipt of treatment included comorbidity burden, marital status, Medicare Part C or Part D coverage, rurality, and race and ethnicity.

CONCLUSIONS AND RELEVANCE: In this cohort study of older adults with mNSCLC, despite advances in therapy in recent decades, almost half of patients never received systemic therapy, and the proportion treated only minimally improved over time. Approximately one-fifth of those with the most favorable clinical profiles did not receive systemic therapy.

PMID: 42096214 [Indexed for MEDLINE]

11. JAMA Oncol. 2026 Jul 9:e262330. doi: 10.1001/jamaoncol.2026.2330.

Consolidative Thoracic Radiotherapy With Atezolizumab Maintenance in Extensive-Stage Small Cell Lung Cancer: The Phase 2 TREASURE Randomized Clinical Trial (AIO-TRK-0320).

IMPORTANCE: Chemoimmunotherapy followed by immunotherapy maintenance is the standard first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), yet data regarding efficacy and safety of consolidative thoracic radiotherapy (TRT) are lacking.

OBJECTIVE:To determine whether combining consolidative TRT withimmunotherapy maintenance in ES-SCLC is safe and improves patients' overall survival (OS) and progression-free survival (PFS).

DESIGN, SETTINGS, AND PARTICIPANTS: This was a multicenter open-label phase 2 randomized clinical trial recruiting patients from September 2020 to August 2022 in Germany and Austria, with the last follow-up visit in September 2024. Eligible patients had ES-SCLC with at least stable disease after induction chemoimmunotherapy (carboplatin-etoposide-atezolizumab). Although the database was locked in April 2025, a post hoc survival update was performed in April 2026. Data were analyzed from April 2025 to April 2026.

INTERVENTIONS: Randomized (1:1) to either atezolizumab maintenance combined with consolidative TRT (30 Gy in 10 fractions) (arm A) or atezolizumab maintenance alone (arm B).

MAIN OUTCOME AND MEASURE: OS (time from randomization to death due to any cause).

RESULTS: Of 96 patients assessed for eligibility, 68 patients were randomized; recruitment was prematurely terminated due to safety concerns. Median OS in the combination arm was numerically shorter compared to atezolizumab only (6.7 months [95% CI, 5.1-9.0] vs 13.4 months [95% CI, 10.7-17.5]; HR, 1.55 [95% CI, 0.90-2.69]; P = .34), while median PFS was similar (2.4 months [95% CI, 1.3-3.9] vs 2.6 months [95% CI, 1.2-3.9]; HR, 0.92 [95% CI, 0.54-1.55]; P = .85). TRT plus atezolizumab was accompanied by higher frequency of severe adverse events (SAEs) (19 patients [61.3%] vs 6 patients [18.2%]; P < .001) and fatal outcomes (6 patients [19.4%] vs 1 patient [3.0%]; P = .04). Safety analysis revealed predominance of infection and respiratory disorder-related SAEs, possibly facilitated by a depletion of lymphocytes observed specifically in patients after TRT, and by a lower single breath diffuse capacity of the lungs for carbon monoxide in patients with fatal AEs in arm A. No further risk factors were identified, given that baseline characteristics were well balanced between both arms and between patients with and without SAEs, including fatal SAEs.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, TRT combined with immunotherapy increased toxic effects in unselected patients with ES-SCLC without survival benefit, presumably due to radiation-induced lymphocyte depletion facilitating infections. Cautious patient selection and further investigation to identify those who may benefit without undue risk are required.

PMID: 42424047

12. JAMA. 2026 Jul 8. doi: 10.1001/jama.2026.8717. Online ahead of print.

Lung Transplant for Refractory Lung-Limited Stage IV Non-Small Cell Lung Cancer.

IMPORTANCE: Patients with medically refractory, lung-limited, stage IV non-small cell lung cancer (NSCLC) often die of progressive respiratory failure. Although lung transplant offers the possibility of organ-level disease extirpation, the surgery has historically not been offered to such patients due to concerns of poor oncological outcomes.

OBJECTIVE: To describe outcomes among patients who underwent lung transplant and examine survival associated with lung transplant compared with medical management alone.

DESIGN, SETTING, AND PARTICIPANTS: This prospective, single-center, registry study included 404 adults. Of 98 adults with medically refractory, lung-limited, stage IV NSCLC, 17 underwent lung transplant and 81 met transplant eligibility criteria but did not undergo transplant due to nonbiologic barriers and were treated with medical management alone. There were 306 adults without cancer who underwent lung transplant for end-stage pulmonary disease. All who underwent lung transplant had respiratory failure. The study was conducted from September 1, 2021, through June 30, 2025; the last day of extended follow-up was January 31, 2026.

EXPOSURES: Lung transplant after contemporary staging and a dissemination-minimizing operative technique was used.

MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival from eligibility evaluation completion in patients with NSCLC who underwent lung transplant vs those with NSCLC who were treated with medical management alone. The secondary outcome was 1-year posttransplant survival (organ stewardship comparison) in patients with NSCLC who underwent lung transplant vs those without cancer who underwent lung transplant.

RESULTS: Among the 98 patients with stage IV NSCLC, the median follow-up from eligibility evaluation completion through June 30, 2025, was 343 (IQR, 191-768) days for the 17 lung transplant recipients (median age, 61.0 [IQR, 48.0-64.0] years; 10 [59%] were women) and the median follow-up was 221 (IQR, 68-386) days for the 81 patients who received medical management alone (median age, 63.4 [IQR, 56.7-68.1] years; 42 [52%] were women). Among the 306 lung transplant recipients without cancer, the median follow-up from transplant was 200 (IQR, 126-496) days (median age, 63.0 [IQR, 55.0-68.8] years; 112 [37%] were women). The Kaplan-Meier estimated 1-year overall survival was 100.0% (95% CI, 63.1%-100.0%) (0 deaths) among the lung transplant recipients with NSCLC vs 40.8% (95% CI, 29.6%-53.1%) (52 deaths) among those with NSCLC who received medical management alone (absolute difference, 59.2 [95% CI, 46.2-71.7] percentage points). The 1-year posttransplant survival was 100% (95% CI, 63.1%-100%) among patients with NSCLC vs 88.1% (95% CI, 83.7%-91.4%) among patients without cancer (absolute difference, 11.9 [90% CI, 9.1-15.5] percentage points). At the extended follow-up (January 31, 2026), 2 of the transplant recipients with stage IV NSCLC had died.

CONCLUSIONS AND RELEVANCE: Among selected patients with medically refractory, lung-limited, stage IV NSCLC and respiratory failure who underwent lung transplant, early survival was favorable. Longer-term follow-up and quality-of-life assessment are needed.

PMID: 42418196

13. Lancet Glob Health. 2026 Jul 2:103971. doi: 10.1016/j.langlo.2026.103971.

Phone-based screening versus home-based screening after tuberculosis in India (TB Aftermath): a multicentre, open-label, randomised, controlled, non-inferiority trial.

BACKGROUND: Tuberculosis survivors and their household contacts are at increased risk for tuberculosis even after treatment completion; however, effective strategies for post-tuberculosis screening remain untested. We aimed to assess whether phone-based screening is non-inferior to home-based screening for tuberculosis after treatment completion in India.

METHODS: In this multicentre, open-label, randomised, controlled, non-inferiority trial, we enrolled tuberculosis survivors (aged >18 years) within 60 days of completing treatment for any form of tuberculosis from six public clinics in Maharashtra, India. Household contacts were enumerated at baseline (all ages). Survivors were randomly assigned (1:1) to receive phone-based or home-based symptom screening at 6 months and 12 months. The trial was powered to identify a difference in the tuberculosis detection rate per 100 person-years among survivors and contacts together (primary outcome), comparing screening groups during the 12 months after survivor treatment completion. We conducted an intention-to-treat analysis with a rate difference non-inferiority margin of 1·70 per 100 person-years based on the upper bound of the 95% CI. We adjusted for household-level clustering of tuberculosis by fitting a multilevel Poisson model. We also conducted a subgroup analysis of detection rates among survivors and contacts separately. This study is registered with ClinicalTrials.gov, NCT04333485 and is completed.

FINDINGS: We enrolled 1076 tuberculosis survivors (537 in the phone-based screening group and 539 in the home-based screening group) and enumerated 3309 contacts (1638 in the phone-based screening group and 1671 in the home-based screening group) between Jan 21, 2021, and Sept 4, 2023. In the 12-month post-treatment period, tuberculosis was detected in 75 (7%) tuberculosis survivors and 30 (1%) contacts: 41 events in the phone-based screening group (rate 1·19 [95% CI 0·82-1·71]) compared with 64 events in the home-based screening group (1·92 [1·37-2·45]). Non-inferiority was reached (rate difference 0·73 [95% CI 0·05-1·41]). Among tuberculosis survivors, the recurrence detection rate was 4·36 (95% CI 2·87-6·34) in the phone-based screening group compared with 8·00 (5·90-10·60) in the home-based screening group (p=0·01). Among contacts, the tuberculosis detection rate was 0·61 (95% CI 0·32-1·07) in the phone-based screening group compared with 0·70 (0·39-1·20) in the home-based screening group (p=0·70).

INTERPRETATION: Risk of tuberculosis remains high for households with a tuberculosis survivor. For detecting tuberculosis among survivors and their household contacts together, phone-based screening was non-inferior to home-based screening. For survivors, the recurrence detection rate was higher in the home-based screening group. Countries with a high burden of recurrence should consider home-based screening among tuberculosis survivors.

PMID: 42392121

14. Lancet Infect Dis. 2026 Jul 27:S1473-3099(26)00351-8. doi: 10.1016/S1473-3099(26)00351-8. Online ahead of print.

Empiric tuberculosis treatment in hospitalised adults with advanced HIV disease in Africa: applying the therapeutic threshold to clinical practice.

Hospitalised adults with advanced HIV disease in sub-Saharan Africa experience high mortality, with tuberculosis, often disseminated and undiagnosed, being a leading cause. Despite this, initiation of antituberculous therapy is frequently delayed pending diagnostic confirmation, which may be unavailable in this population. Evidence from recent trials and cohort studies suggests that even short delays in antituberculous therapy are associated with substantial increases in mortality, whereas empiric therapy might improve survival in people at high risk. Applying the therapeutic threshold framework, the high pre-test probability of tuberculosis in severely ill inpatients with advanced HIV disease often exceeds the threshold at which treatment benefits outweigh risks, even in the absence of confirmatory testing. Although concerns regarding toxicity, drug interactions, and overtreatment are valid, short-term empiric antituberculous therapy appears safe and these risks might be outweighed by the consequences of untreated disease. We argue for a paradigm shift towards earlier empiric antituberculous therapy, with parallel diagnostic evaluation and structured reassessment in selected patients, and for adequately powered randomised controlled trials of empiric therapy powered for mortality.

PMID: 42508442

15. Lancet Infect Dis. 2026 Jul 1:S1473-3099(26)00295-1. doi: 10.1016/S1473-3099(26)00295-1. Online ahead of print.

Global, regional, and national burden of tuberculosis and multidrug-resistant tuberculosis by HIV status, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.

BACKGROUND: Tuberculosis (TB) is the leading global cause of death from a single infectious agent. Recent reductions in global health funding have threatened TB control, making comprehensive assessment of TB, HIV-related TB, and drug-resistant TB burdens before these disruptions essential for shaping effective responses. The WHO End TB Strategy sets targets of a 95% reduction in TB deaths and a 90% reduction in TB incidence between 2015 and 2035. Using results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, this study aims to assess the burden of TB and multidrug-resistant TB (MDR-TB) across 204 countries and territories, and to evaluate progress towards the WHO End TB incidence and mortality targets.

METHODS: We quantified TB mortality using the Cause of Death Ensemble modelling platform with global vital registration, surveillance, verbal autopsy, and minimally invasive tissue sampling data. For TB morbidity estimation, we simultaneously modelled incidence, prevalence, and mortality by age and sex using DisMod-MR 2.1. A population attributable fraction (PAF) approach was applied to stratify morbidity and mortality estimates by HIV and drug-resistance status. We also calculated disability-adjusted life-years (DALYs) as the sum of years of life lost and years lived with disability. For the risk factor analysis, a comparative risk assessment framework was used and PAFs were derived for alcohol use, smoking, and high fasting plasma glucose to determine the proportion of TB burden associated with these risk factors.

FINDINGS: In 2023, there were an estimated 9·11 million (95% uncertainty interval 8·04-10·3) incident cases of all-form TB, 1·22 million (0·98-1·49) deaths, and 54·6 million (43·8-65·5) DALYs globally. HIV-related TB comprised 781 000 (690 000-879 000) incident cases and 210 000 (142 000-279 000) deaths, contributing 11·0 million (7·56-14·3) DALYs. MDR-TB accounted for 466 000 (198 000-1 080 000) incident cases, 102 000 (31 700-238 000) deaths, and 3·96 million (1·31-9·01) DALYs. From 2015 to 2023, global all-form TB incidence rates declined by 19·2% (17·8-20·5) and deaths declined by 22·6% (4·7-35·7); declines were larger for drug-susceptible TB than for MDR-TB. Sub-Saharan Africa and south Asia had the highest mortality burdens in 2023; reductions in all-form TB incidence and mortality were uneven between 2000 and 2023, with limited progress in both measures in Latin America and the Caribbean. Removing smoking, alcohol use, and high fasting plasma glucose would reduce global TB deaths to 768 000 (592 000-970 000) and DALYs to 34·9 million (27·8-43·8) in 2023; MDR-TB deaths would decrease to 77 200 (23 400-183 000) and DALYs to 3·12 million (1·03-7·29).

INTERPRETATION: Global progress towards WHO End TB targets is disparate and fragile. Although many regions achieved meaningful gains, others have stagnated in recent years. The complexity of TB prevention is amplified by divergent MDR-TB trends, the persistent burden of HIV, and growing exposure to modifiable risk factors. Recent volatility in global health financing threatens to further destabilise this vulnerable epidemiological landscape; concerted action is urgently needed to temper disruptions and preserve progress.

PMID: 42385762

16. Am J Respir Crit Care Med. 2026 Jul 1;212(7):1585-1595. doi: 10.1093/ajrccm/aa- mag140.

Role of casual contact in drug-resistant tuberculosis transmission: a molecular

epidemiology study.

RATIONALE: Transmission is the primary driver of tuberculosis (TB) and drug-resistant TB (DR-TB) in high-burden countries; however, where and between whom spread occurs is poorly understood.

OBJECTIVES: We conducted universal whole genome sequencing (WGS) to evaluate the role of casual contact in Mycobacterium tuberculosis transmission.

METHODS: We recruited persons diagnosed with second-line DR-TB (eg, extensively drug-resistant [XDR], pre-XDR-TB) from June 2018 to December 2022 in metropolitan Durban, South Africa. We collected named contacts and GPS coordinates of homes, clinics, and community locations visited regularly before diagnosis. Among participants genotypically clustered by whole genome sequencing (≤12 single-nucleotide polymorphisms), we quantified the proportion attributable to close versus casual contact. Close contact was defined as person-to-person links or overlapping hospitalizations. Casual contact links were based on geographic proximity of homes and community locations, or shared outpatient clinics.

MEASUREMENTS AND MAIN RESULTS: We enrolled 305 of 383 (80%) persons diagnosed with second-line DR-TB. TB isolates were sequenced for 251 (83%) participants; 141 (56%) were genotypically linked, forming 25 clusters (range, 2-49 persons/cluster). Among clustered participants, 69 (49%) were epidemiologically linked by casual contact and 13 (9%) through close contact. Multivariable analysis identified living within 1 km (OR, 17.9), visiting proximate community locations (OR, 1.88), shared outpatient clinic (OR, 1.72), and person-to-person links (OR, 5.38) as significant risk factors associated with genotypic clustering.

CONCLUSIONS: Casual contact in community locations accounted for half of transmission among genotypic clusters in a high-burden setting. Efforts to curb TB will require a greater emphasis on community-based measures to identify cases from casual contact or undetected intermediate cases, in addition to the current mainstay of contact tracing.

PMID: 42089682 [Indexed for MEDLINE]

17. Cancer Discov. 2026 Jul 1;16(7):1436-1455. doi: 10.1158/2159-8290.CD-25-0470.

LIF-Induced Tumor Plasticity Establishes an Immunosuppressive Myeloid Niche in LKB1-Mutant Lung Cancer.

LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression.

SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.

PMID: 42008781 [Indexed for MEDLINE]

18. J Clin Oncol. 2026 Jul;44(19):1833-1844. doi: 10.1200/JCO-25-03026.

Overcoming Primary and Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer: Mechanisms, Challenges, and Emerging Strategies.

Acquired resistance (AR) to immune checkpoint inhibitors (ICIs) remains a major obstacle to durable clinical benefit in non-small cell lung cancer (NSCLC). Emerging after initial responses, AR reflects tumor evolution, immune escape, and metabolic reprogramming. Key mechanisms may include impaired antigen presentation (β2-microglobulin, human leukocyte antigen mutations), T-cell exhaustion, and remodeling of the tumor microenvironment (TME). In this review, we summarize the current understanding of ICIs resistance and highlight therapeutic strategies under investigation to overcome it. Novel approaches include next-generation ICIs targeting TIGIT and LAG-3, epigenetic modulators (HDAC, DNMT inhibitors), and metabolic agents relevant to STK11 and KEAP1 mutations. Additional strategies aim to reprogram the TME through AXL or multikinase inhibition, tumor-treating fields, and cytokine- and/or gene-based therapies. Cellular immunotherapies (tumor-infiltrating lymphocytes, T-cell receptors, chimeric antigen receptor-T), antibody-drug conjugates, and vaccines offer complementary means to restore antitumor immunity. Advancing the field will require biomarker-driven patient selection and rational combinations to overcome AR and achieve more durable, personalized immunotherapy outcomes in NSCLC.

PMID: 42172565 [Indexed for MEDLINE]

19. Cancer Cell. 2026 Jul 13;44(7):1401-1417.e9. doi: 10.1016/j.ccell.2026.05.020.

Targeting TROP2 in drug-tolerant persister cells delays EGFR tyrosine kinase inhibitor resistance in non-small-cell lung cancer.

Drug-tolerant persister (DTP) cells play a key role in the development of resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Through comprehensive analyses, we identify that TROP2 is dynamically upregulated during TKI-induced DTP formation and functionally contributes to DTP maintenance. Mechanistically, c-Myc acts as a transcriptional repressor of TROP2, and TKI-mediated MAPK pathway inhibition reduces c-Myc levels, leading to TROP2 upregulation. Importantly, combining the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab tirumotecan (sac-TMT) with osimertinib effectively suppresses DTP emergence and delays tumor relapse in preclinical models. An ongoing phase 2 trial evaluating first-line sac-TMT plus osimertinib combination therapy in patients with advanced EGFR-mutant NSCLC shows preliminary efficacy. Together, our findings establish TROP2 as a therapeutically actionable vulnerability in DTP cells and support the clinical development of TROP2-ADC combined with EGFR-TKI as a first-line strategy to delay TKI resistance and improve outcomes in EGFR-mutant NSCLC.

PMID: 42314664 [Indexed for MEDLINE]

20. Cancer Cell. 2026 Jul 27:S1535-6108(26)00310-7. doi: 10.1016/j.ccell.2026.07. 001.

Tumor-infiltrating plasma cell profiling after PD-1 blockade reveals tumor-specific antibodies.

The role of tumor-infiltrating B cells (TIL-Bs) in shaping anti-tumor responses in the context of immune checkpoint blockade remains incompletely understood. Here, we interrogate the humoral response in resected lung tumors from patients with non-small cell lung cancer (NSCLC) treated with neoadjuvant PD-1 blockade. We find that tumors orchestrate tertiary lymphoid structures with CD138+ plasma cells, from which we clone recombinant monoclonal antibodies (mAbs) using B cell receptors (BCRs) exhibiting somatic hypermutation and class switching. Several mAbs bind cell-surface citrullinated proteins, characteristic of cancer cells. Chimeric antigen receptor (CAR) T redirected with the soluble chain fragment variable (scFv) of our lead candidate antibody (PC-1) specifically target tumor cells and tumor-promoting myeloid cells in vivo without off-target activity. Moreover, ablation of the citrullination enzyme PADI2 in tumor-bearing mice eliminates reactivity to PC-1 and cytotoxic killing by the CAR. Our results implicate a therapeutic potential for tumor-infiltrating plasma cells that may be harnessed for cancer treatment.

PMID: 42508408

21. JAMA Oncol. 2026 Jul 1;12(7):762-766. doi: 10.1001/jamaoncol.2026.1199.

Temporal Trends in Lung Cancer Cases Diagnosed at Early Stage.

IMPORTANCE: Since December 2013, the US Preventive Services Task Force has recommended lung cancer screening for adults at high risk of developing lung cancer because of their age and smoking history. Increased uptake in lung cancer screening may be reflected in changes in the stage at which lung cancer is diagnosed.

OBJECTIVE: To examine the percentage of lung cancer cases diagnosed at an early stage, visualizing temporal patterns with heat maps.

DESIGN, SETTING, AND PARTICIPANTS: This descriptive surveillance study used US Cancer Statistics incidence data to identify US adults who were diagnosed with malignant lung cancer from 2003 to 2022. Data were analyzed from November 14 to November 30, 2025.

MAIN OUTCOMES AND MEASURES: Percentage of lung cancers diagnosed at early stage, stratified by year of diagnosis, age at diagnosis, and state of residence.

RESULTS: From 2003 to 2022, 4 363 687 new lung cancer cases were reported in the US. The percentage diagnosed at early stage increased slowly from 17.6% (95% CI, 17.5%-17.8%) in 2003 to 20.2% (95% CI, 20.0%-20.4%) in 2014, increased sharply from 21.4% (95% CI, 21.2%-21.6%) in 2015 to 24.6% (95% CI, 24.4%-24.8%) in 2016, then increased steadily to 30.1% (95% CI, 29.9%-30.3%) in 2022. The percentage diagnosed at early stage increased in all states, beginning around 2016 in most states. In 2003, the percentage diagnosed at early stage ranged from 11.2% (95% CI, 8.5%-14.6%) to 24.0% (95% CI, 22.7%-25.4%); by 2022, this range was 22.0% (95% CI, 18.9%-25.5%) to 40.2% (95% CI, 36.7%-43.9%).

CONCLUSIONS AND RELEVANCE: This descriptive surveillance study showed that since lung cancer screening was recommended in 2013, more people with lung cancer are being diagnosed early, when treatment is more effective and more treatment options are available. Population-based survey data indicate that fewer than 1 in 5 eligible persons reported being up to date with lung cancer screening in 2024. Strengthening awareness about the benefits of lung cancer screening and supporting uptake remain important strategies for cancer prevention and control.

PMID: 42133301 [Indexed for MEDLINE]

22. J Clin Oncol. 2026 Jul 16:JCO2502517. doi: 10.1200/JCO-25-02517.

Durvalumab With Radiation Therapy in Patients With Inoperable Locally Advanced Non-Small Cell Lung Cancer Ineligible for Concurrent Chemoradiotherapy (DART).

PURPOSE: Concurrent platinum-based chemotherapy and radiation therapy (cCRT) followed by consolidative durvalumab is the standard of care (SoC) for fit patients with inoperable, locally advanced non-small cell lung cancer (LA-NSCLC). However, no SoC exists for patients who are cCRT-ineligible because of age, comorbidities, or frailty. Here, we investigated the efficacy and adverse events (AEs) of concurrent and consolidative durvalumab with definitive radiation therapy (RT) without chemotherapy.

METHODS: In this multicenter, single-arm, prospective phase II study, patients received conventionally fractionated RT plus concurrent and consolidative durvalumab (1,500 mg fixed dose once every 4 weeks) for up to 12 months. The primary end point was 2-year progression-free survival (PFS) of 36% compared with historical results of 20% with sequential CRT (86% power). Additional end points included overall survival (OS) and cancer-specific survival (CSS).

RESULTS: Fifty-eight patients (median age 82 years [IQR, 76-86]; 16 [28%] PD-L1-negative; eight [14%] Eastern Cooperative Oncology Group [ECOG] score 2; 46 [79%] ECOG score 1; four [7%] ECOG score 0) were treated per protocol. The study met its primary end point with a 2-year PFS of 39% (one-sided CI, 29 to 100) and a 2-year OS of 54%. Better performance status and PD-L1 positivity were associated with improved PFS; better ECOG was associated with improved OS; PD-L1 positivity was associated with better CSS. Grade 3/4 treatment-related AEs occurred in 12 (21%) patients. Grade 5 AEs occurred in four (7%) patients (radiation pneumonitis (n = 2) and cardiac arrest (n = 2)). Durvalumab was discontinued early because of AEs in 18 (31%) patients.

CONCLUSION: Thoracic RT with concurrent and consolidative durvalumab is a promising treatment option for cCRT-ineligible patients with LA-NSCLC, demonstrating better PFS with a favorable safety profile compared with historical controls.

PMID: 42462186

23. J Clin Oncol. 2026 Jul 27:JCO2502777. doi: 10.1200/JCO-25-02777.

SKYSCRAPER-01: Tiragolumab in Combination With Atezolizumab in Previously Untreated PD-L1-High, Locally Advanced, Unresectable or Metastatic Non-Small Cell Lung Cancer.

PURPOSE: Tiragolumab plus atezolizumab has shown encouraging survival outcomes in metastatic non-small cell lung cancer (NSCLC), primarily in patients with PD-L1-high tumors. We further evaluated the combination of tiragolumab plus atezolizumab in the phase III SKYSCRAPER-01 study.

METHODS: Patients with untreated, locally advanced unresectable/metastatic PD-L1-high (by central laboratory testing) NSCLC were randomly assigned 1:1 to receive either tiragolumab (600 mg) plus atezolizumab (1,200 mg) or placebo plus atezolizumab (1,200 mg) intravenously in 21-day cycles until disease progression, loss of clinical benefit, or unacceptable toxicity. Primary end points were investigator-assessed progression-free survival (INV-PFS) and overall survival (OS) in the primary analysis set (PD-L1-high per 22C3 assay).

RESULTS: Five hundred twenty-one patients were randomly assigned to either the tiragolumab plus atezolizumab group (n = 262) or the placebo plus atezolizumab group (n = 259). At the primary PFS analysis (Mar 12, 2022; median follow-up 9.9 months [IQR, 6.2-13.8]), median INV-PFS was 7.0 months (95% CI, 5.6 to 9.8) with tiragolumab plus atezolizumab and 5.6 months (95% CI, 4.4 to 7.0) with placebo plus atezolizumab (hazard ratio [HR], 0.78 [95% CI, 0.63 to 0.97]; P = .02 [nonsignificant]). At the final OS analysis (Sept 24, 2024; median follow-up 17.9 months [IQR, 6.7-39.0]),median OS was 23.1 months (95% CI, 17.7 to 28.8) with tiragolumab plus atezolizumab and 16.9 months (95% CI, 14.6 to 21.3) with placebo plus atezolizumab (HR, 0.87 [95% CI, 0.7 to 1.1]; P = .22 [nonsignificant]). Overall, 41.2% (n = 110/267) and 33.8% (n = 89/263) of patients experienced grade 3-4 adverse events with tiragolumab plus atezolizumab and placebo plus atezolizumab, respectively. Four and two treatment-related deaths occurred in each group, respectively.

CONCLUSION: Tiragolumab plus atezolizumab did not demonstrate a statistically significant INV-PFS or OS benefit over atezolizumab in patients with previously untreated PD-L1-high NSCLC.

PMID: 42507968

24. J Clin Oncol. 2026 Jul 24:JCO2600243. doi: 10.1200/JCO-26-00243.

Izalontamab Brengitecan (Iza-Bren), a First-in-Class EGFR-HER3 Bispecific Antibody-Drug Conjugate in Extensive-Stage Small Cell Lung Cancer: Results From a Phase Ib Study.

PURPOSE: Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, with limited treatment options beyond frontline chemo-immunotherapy. Izalontamab brengitecan (iza-bren, BL-B01D1) is a first-in-class bispecific antibody-drug conjugate cotargeting epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3). We expanded the SCLC cohort to further evaluate the efficacy and safety of iza-bren in patients with extensive-stage SCLC (ES-SCLC).

METHODS: This open-label, multicenter, dose-expansion phase Ib study (ClinicalTrials.gov identifier: NCT05194982) enrolled patients with ES-SCLC who had progressed on prior systemic therapies. Patients received iza-bren 2.5 mg/kg once daily on days 1 and 8 of each 3-week cycle. The primary end points were objective response rate (ORR) and safety/tolerability. Secondary end points included disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory end point included the assessment of potential associations between EGFR/HER3 expression and clinical outcomes.

RESULTS: As of December 5, 2024, 52 patients were enrolled. The ORR was 48.1% (95% CI, 34.0 to 62.4), with a median PFS of 4.1 months (95% CI, 3.0 to 5.5) and a median OS of 12.2 months (95% CI, 9.1 to 13.2). In patients who received iza-bren as second-line treatment (n = 22), the ORR was 72.7% (95% CI, 49.8 to 89.3), median PFS 6.2 months (95% CI, 3.7 to 8.2), and median OS 15.0 months (95% CI, 8.7 to not reached). The most common treatment-related adverse events were hematologic toxicities (neutropenia, thrombocytopenia, anemia, and leukopenia). Exploratory biomarker analysis suggested that positive HER3 expression may be associated with better treatment response.

CONCLUSION: Iza-bren showed encouraging antitumor activity in relapsed ES-SCLC, particularly in the second-line setting. A phase III randomized controlled trial of iza-bren compared with topotecan (ClinicalTrials.gov identifier: NCT06500026) is ongoing.

PMID: 42497381

25. Lancet Respir Med. 2026 Jul 7:S2213-2600(26)00142-6. doi: 10.1016/S2213-2600(26)00142-6.

Ifebemtinib plus garsorasib as first-line treatment for KRAS(G12C)-mutated non-small-cell lung cancer in China: a multicentre, single-arm expansion cohort from a phase 1b/2 trial.

BACKGROUND: Ifebemtinib, a potent selective oral inhibitor of FAK, has shown preclinical synergistic activity with KRASG12C inhibitors. Garsorasib is a novel KRASG12C inhibitor approved in China for patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC). This study aimed to evaluate the safety and efficacy of ifebemtinib plus garsorasib in KRASG12C-mutated solid tumours.

METHODS: This multicentre study had a phase 1b component to establish the recommended phase 2 dose and a phase 2 multitumour expansion. Here, we report the results of the single-arm, Simon's two-stage cohort of first-line KRASG12C-mutated NSCLC from phase 2 expansion. The study was conducted at eight sites in China. Eligible patients were adults with pathologically confirmed locally advanced or metastatic NSCLC who were harbouring a KRASG12C mutation, were treatment-naive, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Enrolled patients received ifebemtinib (100 mg orally once a day) in combination with garsorasib (600 mg orally twice a day) in a 21-day cycle until disease progression, intolerable toxicity, withdrawal of consent, initiation of new therapies, or death. The primary endpoint was objective response rate (ORR), as assessed by investigators, in all patients who received at least one dose of study treatment. The same population was included in safety analyses. This study is registered with ClinicalTrials.gov (NCT06166836 and NCT05379946) and is active but not recruiting.

FINDINGS: Between April 21, 2023, and Dec 27, 2023, 33 first-line patients with NSCLC (two [6%] female and 31 [94%] male) were enrolled and received at least one dose of ifebemtinib plus garsorasib. As of Sept 16, 2025, median follow-up duration was 21·5 months (IQR 21·0-23·9). Confirmed ORR was 82% (27 of 33 patients; 95% CI 64·5-93·0). All 33 (100%) patients reported treatment-emergent adverse events, with 11 (33%) patients experiencing grade 3 or 4 events, of which eight (24%) were related to study drugs. The most frequent treatment-emergent adverse events of grade 3-4 were grade 3 proteinuria, diarrhoea, anaemia, hypertension, and pneumonia, each occurring in two (6%) of 33 patients. Serious adverse events occurred in nine (27%) of 33 patients, with intracranial haemorrhage and pneumonia being the only events reported in at least two patients (two [6%] each). No treatment-related deaths were reported.

INTERPRETATION: The dual-oral chemotherapy-free regimen of ifebemtinib plus garsorasib had encouraging efficacy with a manageable safety profile as first-line treatment for KRASG12C-mutated NSCLC. A randomised phase 3 study has been initiated to further validate these findings against standard-of-care in the first-line setting (NCT07174908).

PMID: 42413526

26. Lancet Oncol. 2026 Aug;27(8):1043-1056. doi: 10.1016/S1470-2045(26)00191-9.

Differential impact of proton pump inhibitors and antibiotics on immunotherapy efficacy after chemoradiotherapy in locally advanced non-small-cell lung cancer: a post-hoc analysis of the PACIFIC trial.

BACKGROUND: Baseline exposure to antibiotics and proton pump inhibitors has been associated with reduced efficacy of immune checkpoint inhibitors in patients with advanced tumours, possibly through gut microbiome disruption. Whether this outcome extends to those with earlier-stage disease remains unclear. We aimed to assess the association of baseline antibiotics and proton pump inhibitors with progression-free survival and overall survival in patients with unresectable stage III non-small cell lung cancer (NSCLC).

METHODS: PACIFIC was a randomised, double-blind, placebo-controlled phase 3 trial done in patients aged 18 years or older with unresectable stage III squamous or non-squamous NSCLC, WHO performance status 0-1, and no progression after two or more cycles of concurrent chemoradiotherapy. Patients were randomly assigned (2:1) to durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months or placebo, starting 1-42 days after chemoradiotherapy; patients were stratified by age, sex, and smoking history. This post-hoc analysis was based on the final 5-year data cutoff date of the completed trial and included the treated population with consent for exploratory analyses. Co-primary endpoints were progression-free survival and overall survival, assessed according to baseline exposure to proton pump inhibitors and systemic antibiotics. This trial is registered on ClinicalTrials.gov (NCT02125461).

FINDINGS: Between May 9, 2014, and April 22, 2016, 713 patients were randomly assigned; 660 were included in this post-hoc analysis, of whom 449 received durvalumab and 211 received placebo; 203 (30·8%) were female and 453 (68·6%) were male. Race was reported as Asian in 153 (23·1%) patients, Black or African American in five (0·7%), White in 424 (64·2%), and unknown in 78 (11·8%). Baseline proton pump inhibitor exposure was recorded in 263 (40%) of 660 patients and antibiotic exposure was recorded in 69 (10%). Median follow-up in the pooled population was 62·4 (IQR 61·9-63·2) months. In the durvalumab group baseline exposure to proton pump inhibitors was associated with shorter progression-free survival (9·4 months [95% CI 7·6-13·7] vs 17·2 months [15·4-23·2]; hazard ratio [HR] 1·57 [95% CI 1·28-1·93]; p<0·0001) and overall survival (33·0 months [95% CI 21·9-46·7] vs 57·9 months [48·7-not computable (NC)]; HR 1·66 [95% CI 1·30-2·13]; p<0·0001) compared to no exposure to proton pump inhibitors, while baseline exposure to antibiotics was associated with shorter progression-free survival (9·2 months [95% CI 4·9-18·1] vs 15·6 months [13·6-17·6]; HR 1·50 [95% CI 1·08-2·10]; p=0·016) compared to no exposure to antibiotics, but there was no significant change in overall survival (37·7 months [95% CI 18·8-NC; 28 events] vs 49·2 months [39·7-57·3]; HR 1·33 [95% CI 0·90-1·97]; p=0·16). In the placebo group, neither proton pump inhibitor exposure nor antibiotic exposure was associated with changes in progression-free survival and overall survival. Interactions between treatment and proton pump inhibitors for progression-free survival (p=0·023) and overall survival (p<0·0001) were significant, but not for antibiotics.

INTERPRETATION: Baseline exposure to proton pump inhibitors and antibiotics was associated with inferior outcomes with durvalumab, but not with placebo, consistent with potential attenuation of the benefit of durvalumab with proton pump inhibitors and antibiotics in patients with unresectable stage III NSCLC.

PMID: 42398520

27. J Clin Oncol. 2026 Jul 1:JCO2503128. doi: 10.1200/JCO-25-03128.

Efficacy and Tolerability of Zenocutuzumab in Advanced NRG1 Fusion-Positive Cholangiocarcinoma: Results From the eNRGy Phase II Trial.

PURPOSE: Presently, to our knowledge, there are no approved targeted therapies for neuregulin 1 gene fusion-positive (NRG1+) cholangiocarcinoma. Zenocutuzumab, a HER2 × HER3 bispecific antibody, is approved for previously treated, advanced/ metastatic NRG1+ non-small cell lung cancer and pancreatic adenocarcinoma. Here, we report results for 22 patients with NRG1+ cholangiocarcinoma in the eNRGy trial.

METHODS: eNRGy is a single-arm, phase II study of zenocutuzumab in advanced NRG1+ solid tumors. Patients were age 18 years and older and previously treated with or unsuitable for standard therapy. Zenocutuzumab 750 mg was administered intravenously once every 2 weeks. The primary end point was investigator-assessed overall response rate (ORR; RECIST v1.1). Secondary end points included duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), and safety.

RESULTS: As of July 31, 2025, 22 patients (median age 57.5 years) with advanced NRG1+ cholangiocarcinoma were enrolled and had received a median of 1.0 (range, 0-6) prior therapies. In the 18 patients with tumor subtype data available, all had intrahepatic cholangiocarcinoma. Three patients did not meet the protocol-defined criteria for inclusion in the efficacy analysis. Seven of 19 patients achieved a response, resulting in an ORR of 36.8% (95% CI, 16.3 to 61.6). The median DOR was 7.4 months and the median time to response was 1.9 months. The CBR was 57.9% (95% CI, 33.5 to 79.7). Median PFS was 9.2 months (95% CI, 3.9 to 11.1). Most treatment-related adverse events (TRAEs) were grade 1 and 2, and the most common were diarrhea (27.3%), fatigue (18.2%), and nausea (13.6%). One patient had a grade 3 TRAE of anemia. No patients discontinued treatment due to an AE.

CONCLUSION: Zenocutuzumab demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced NRG1+ cholangiocarcinoma.

PMID: 42385125

28. Lancet Oncol. 2026 Jul;27(7):785-794. doi: 10.1016/S1470-2045(26)00090-2.

Aumolertinib with or without chemotherapy in EGFR-mutated advanced non-small-cell lung cancer (AENEAS2): an open-label, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Although third-generation epidermal growth-factor receptor (EGFR)-tyrosine-kinase inhibitors (TKIs) are standard first-line therapies for patients with advanced EGFR-mutated non-small-cell lung cancer (NSCLC), their effectiveness is often limited by the emergence of drug resistance and subsequent disease progression. Given the previously established clinical efficacy and adverse event profile of aumolertinib, we aimed to evaluate the efficacy and adverse event profile of aumolertinib in combination with platinum-based chemotherapy versus aumolertinib monotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC patients with EGFR-sensitive mutations.

METHODS: The open-label, multicentre, randomised, controlled, phase 3 AENEAS2 trial was done across 60 hospitals in China. Patients aged at least 18 years with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1; treatment-naive; histologically or cytologically confirmed locally advanced or metastatic NSCLC harbouring EGFR-sensitive mutations (ex19del/L858R with or without other EGFR mutations) were eligible. Brain metastases were allowed if neurologically stable. Previous EGFR-TKI therapy was an exclusion criterion. Patients were randomly assigned (1:1) with block randomisation (block size of 6), stratified by EGFR mutation type and baseline brain metastasis, to receive aumolertinib monotherapy (110 mg orally once a day) or combination therapy (aumolertinib 110 mg orally once a day plus pemetrexed 500 mg/m2 intravenously with cisplatin [75 mg/m2] or carboplatin [area under the plasma concentration-time curve 5] intravenously on day 1 of 21-day cycles for 4-6 cycles), followed by maintenance therapy (aumolertinib 110 mg orally once a day and pemetrexed 500 mg/m2 intravenously once every 3 weeks). The primary endpoint was progression-free survival assessed by blinded independent central review

(BICR; RECIST version 1.1). Efficacy was analysed in the full-analysis set, which included all randomly assigned patients, and safety was analysed in patients who received at least one dose of the actual trial treatment. The trial is registered at ClinicalTrials.gov, NCT04923906, and is ongoing, but closed to enrolment.

FINDINGS: Between Aug 4, 2021, to June 18, 2024, of 1011 patients assessed for eligibility, 624 randomly assigned patients (median age 59·0 years [IQR 52·0-66·0]; 337 [54%] were female, 287 [46%] were male) were randomly assigned. 310 (50%) patients received combination therapy and 314 (50%) received monotherapy. As of the data cutoff date (June 18, 2024), the median follow-up was 23·4 months (IQR 20·5-26·5), In the full-analysis set, median BICR-assessed progression-free survival was 28·9 months (95% CI 26.3, NA) in the combination therapy versus 18·9 months (17·8-21·1) in the monotherapy (hazard ratio [HR] 0·47, 95% CI 0·37-0·60; log-rank p<0·0001). The most common grade 3-4 adverse events (occurring in at least 20% in any group) were neutrophil count decreased (168 [55%] of 304 in the combination group versus four [1%] of 316 in monotherapy group), white blood cell count decreased (103 [34%] vs one [<1%]), and platelet count decreased (62 [20%] vs two [1%]). Serious adverse events occurred in 109 (36%) patients in the combination group and 53 (17%) in the monotherapy group, the most common of which were platelet count decreased (22 [7%] vs 0), neutrophil count decreased (17 [6%] vs 0), white blood cell count decreased (13 [4%] vs 0), and anaemia (ten [3%] vs two [1%]). Treatment-related deaths occurred in one (<1%) patient in the combination group (encephalopathy) and two (1%) in the monotherapy group (pulmonary embolism and respiratory failure with circulatory collapse).

INTERPRETATION: Aumolertinib in combination with chemotherapy significantly improved progression-free survival. Although this regimen was associated with increased toxicity, the side-effects were managed with dose adjustment and supportive treatment aligned with clinical practice. Long-term follow-up is required to assess overall survival. The AENEAS2 study provides evidence to guide clinical practice regarding EGFR-TKIs and their combination use in treating patients with advanced EGFR-mutated NSCLC.

FUNDING: Jiangsu Hansoh Pharmaceutical Group, and the Collaborative Innovation Center for Clinical and Translational Science by Ministry of Education & Shanghai.

PMID: 42296979 [Indexed for MEDLINE]

29. JAMA Oncol. 2026 Jul 1;12(7):753-761. doi: 10.1001/jamaoncol.2026.1548.

PD-(L)1 Inhibitor Monotherapy vs Chemoimmunotherapy for Advanced NSCLC With High PD-L1 Expression: A Systematic Review and Meta-Analysis.

IMPORTANCE: For patients with advanced non-small cell lung cancer (NSCLC) and programmed cell death 1 ligand 1 (PD-L1) expression of 50% or higher, programmed cell death 1 protein or PD-L1 (PD-[L]1) inhibitor monotherapy is commonly used as first-line therapy; however, whether adding chemotherapy improves outcomes in this population remains unknown.

OBJECTIVE: To compare overall survival (OS) and progression-free survival (PFS) associated with PD-(L)1 inhibitor monotherapy vs chemoimmunotherapy in treatment-naive patients with advanced NSCLC and high PD-L1 expression.

DATA SOURCES: PubMed, Embase, and major oncology conference proceedings were searched for phase 3 randomized clinical trials (RCTs) published before August 3, 2025.STUDY SELECTION: Eligible studies were phase 3 RCTs that enrolled patients with untreated advanced NSCLC, evaluated PD-(L)1 inhibitor monotherapy or chemoimmunotherapy vs chemotherapy alone, and reported outcomes in patients with high PD-L1 expression.

DATA EXTRACTION AND SYNTHESIS: Hazard ratios (HRs) for OS and PFS were extracted from published studies and synthesized using inverse variance methods. Additional analyses included meta-regression, network meta-analysis, and reconstructed individual patient data from published Kaplan-Meier curves.

MAIN OUTCOMES AND MEASURES: Primary outcome was OS; secondary outcome was PFS.

RESULTS: Among 24 trials including 5546 patients with PD-L1-high NSCLC, 16 evaluated chemoimmunotherapy and 8 PD-(L)1 inhibitor monotherapy. Compared with chemotherapy, survival was improved by both chemoimmunotherapy (OS: HR, 0.63 [95% CI, 0.56-0.72]; P < .001; PFS: HR, 0.44 [95% CI, 0.39-0.49]; P < .001) and PD-(L)1 inhibitor monotherapy (OS: HR, 0.74 [95% CI, 0.69-0.80]; P < .001; PFS: HR, 0.70 [95% CI, 0.65-0.76]; P < .001). Tests for subgroup differences suggested improved benefit with chemoimmunotherapy compared to PD-(L)1 inhibitor monotherapy (OS: χ21 = 4.1; P = .04; I2 = 75.8%; PFS: χ21 = 48.1; P < .001; I2 = 97.9%), consistent with meta-regression analyses (OS: HR, 0.85 [95% CI, 0.72-1.00]; P = .048; PFS: HR, 0.61 [95% CI, 0.50-0.75]; P < .001) and network meta-analyses (OS: HR, 0.85 [95% CI, 0.73-0.99]; PFS: HR, 0.61 [95% CI, 0.50-0.75]). In the reconstructed individual patient data analysis, median OS was longer with chemoimmunotherapy (n = 704 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (29.2 months [95% CI, 25.2-35.4] vs 19.8 months [95% CI, 18.3-21.7]; HR, 0.74 [95% CI, 0.66-0.82]; P < .001). Similarly, median PFS was significantly longer with chemoimmunotherapy (n = 701 patients) compared to PD-(L)1 inhibitor monotherapy (n = 1706 patients) (11.3

months [95% CI, 10.3-13.5] vs 6.8 months [95% CI, 6.2-7.1]; HR, 0.67 [95% CI, 0.60-0.75]; P < .001).

CONCLUSIONS AND RELEVANCE: In this meta-analysis of phase 3 RCTs, chemoimmunotherapy was associated with significantly improved OS and PFS compared with PD-(L)1 inhibitor monotherapy in patients with advanced NSCLC and high PD-L1 expression. Prospective trials are needed to confirm these findings.

PMID: 42240993 [Indexed for MEDLINE]

30. Cell Metab. 2026 Jul 7;38(7):1460-1477.e8. doi: 10.1016/j.cmet.2026.05.005.

IRG1/itaconate rewires macrophage and lung tumor metabolism through G6PD inhibition.

Tumor-associated macrophages (TAMs) possess both tumor-promoting and tumor-inhibiting roles. Here, we explore TAMs' anti-tumor functions, focusing on the immune responsive gene 1 (IRG1) and its product, itaconate, in lung cancer development. Spatial metabolomics reveals that endogenous itaconate is markedly depleted within lung tumor regions compared with adjacent non-tumor tissue. Single-cell RNA sequencing shows that macrophages are the primary cells expressing IRG1 in human and mouse lung tumors. Both IRG1 knockout and transplantation of IRG1-depleted bone marrow leads to increased lung tumor growth in various mouse lung tumor models. Additionally, 4-octyl itaconate (Octyl Ita) reduces tumor growth in vitro, in vivo, and in ex vivo human tumor precision-cut lung slices. An integrated multi-omics analysis shows that IRG1/itaconate causes a metabolic shift in cancer cell and pro-tumor macrophages, mainly by inhibiting the pentose phosphate pathway (PPP) through targeting glucose-6-phosphate dehydrogenase (G6PD) activity, thereby suppressing cancer cell growth and transforming pro-tumor macrophages into anti-tumor macrophages. Thus, leveraging IRG1/itaconate's tumor-suppressive effects or using Octyl Ita could be a novel lung cancer therapy.

PMID: 42235511 [Indexed for MEDLINE]

31. Science. 2026 Jul 30;393(6810):aef5438. doi: 10.1126/science.aef5438.

Enabling sustainable supply of the essential cancer medicines etoposide and teniposide in yeast.

Lignans constitute a diverse family of plant metabolites with therapeutic potential. Among them, podophyllotoxin-type aryltetralin lignans serve as precursors for etoposide and teniposide. Etoposide is an essential anticancer medicine approved for first-line treatment of small cell lung cancer, whereas teniposide is used for treatment of leukemia and some brain tumors. Currently, these drugs depend on extraction of precursors from the endangered plant Sinopodophyllum hexandrum, followed by chemical transformations. By identifying key glycosyltransferases and executing more than 60 genetic edits involving 45 heterologous enzymes, the complex biosynthetic pathway of podophyllotoxin-type lignans was reconstructed in yeast. In this study, we established a chemoenzymatic route that streamlines the synthesis of etoposide and teniposide through a single chemical step from biosynthetic precursor 4'-demethyl-epipodophyllotoxin-4-O-glucoside, which enables a secure supply chain of these essential medicines.

PMID: 42531388 [Indexed for MEDLINE]

32. Science. 2026 Jul 2;393(6806):90-97. doi: 10.1126/science.adz4196.

A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.

Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.

PMID: 42391376 [Indexed for MEDLINE]

33. Cell. 2026 Jul 9;189(14):4241-4259.e9. doi: 10.1016/j.cell.2026.05.031.

Cellular architecture and neighborhood-informed virtual spatial tumor profiling from histopathology.

The tumor microenvironment (TME) critically shapes disease progression and therapeutic resistance. However, a comprehensive understanding of its spatial architecture remains elusive, and clinical translation is challenging. Here, we present cellular architecture and neighborhood-informed virtual AI-driven spatial profiling (CANVAS), an artificial intelligence platform that infers tumor ecological habitats from hematoxylin and eosin (H&E) histopathology. Built on an atlas of over 18 million cells profiled by 41-plex spatial proteomics across 457 patients with non-small cell lung cancer, CANVAS establishes 10 reproducible cellular neighborhoods (CNs) capturing conserved spatial organization of the TME. Through multimodal alignment and foundation-model-based morphological encoding, CANVAS predicts CN-anchored habitat structures from H&E slides and enables clinical evaluation in over 5,000 patients spanning 9 cancer types. Across patient cohorts, CANVAS supports prognostic modeling, spatial ecotype stratification, and immunotherapy outcome prediction. These results establish CANVAS as a clinically scalable platform for spatial profiling, bridging single-cell analysis to population-level insight and enabling precision oncology.

PMID: 42302781 [Indexed for MEDLINE]

34. Science. 2026 Jul 16;393(6808):eady1678. doi: 10.1126/science.ady1678.

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

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

PMID: 42462020 [Indexed for MEDLINE]

35.Nat Med. 2026 Jul;32(7):2410-2419. doi: 10.1038/s41591-026-04469-5.

Electronic cigarette use after smoking cessation and lung cancer risk.

Electronic cigarettes (e-cigarettes) have gained popularity as a less harmful alternative to conventional cigarettes, yet their associations with lung cancer risk after smoking cessation remain uncertain. Here we evaluated 4,524,895 adults with a conventional smoking history who participated in the Korean National Health Screening Program in 2018 (baseline), with prior records from 2012-2014. Participants were classified as current smokers, short-term quitters or long-term quitters, and followed up to December 2023. Daily e-cigarette use at baseline was used to define post-cessation e-cigarette use. Lung cancer incidence and lung cancer-specific death (LCSD) were assessed using multivariable Cox models. Over 24,182,543 person-years, 35,887 lung cancers and 12,807 LCSD events occurred. Compared with complete quitters, e-cigarette use after smoking cessation was associated with higher risks of lung cancer incidence (adjusted hazard ratio (aHR) 1.56, 95% confidence interval (CI) 1.24-1.97) and LCSD (aHR 2.00, 95% CI 1.28-3.15). Associations were directionally consistent in short-term and long-term quitters and were prominent in the high-risk subgroup (incidence: aHR 1.91, 95% CI 1.44-2.53; LCSD: aHR 1.92, 95% CI 1.13-3.24). Although causality cannot be established, these findings suggest that e-cigarette use after smoking cessation may attenuate the benefits of complete cessation for lung cancer prevention.

PMID: 42260103 [Indexed for MEDLINE]