PubMed：

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

Filters applied: from 2026/04/01 - 2026/04/30.

1. Nature. 2026 Apr 29. doi: 10.1038/s41586-026-10428-4. Online ahead of print.

Evolutionary characterization of lung cancer metastasis.

Limited understanding of the biological processes that govern metastatic dissemination hinders its prevention and treatment1. Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional driver alterations and genome doubling events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC-which tends to be underestimated in single metastasis biopsies-and identifies genomic and clinical mediators of metastatic progression.

PMID: 42056508

2. N Engl J Med. 2026 Apr 30;394(17):1675-1684. doi: 10.1056/NEJMoa2516969. Epub 2026 Apr 15.

First-Line Zongertinib in Advanced HER2-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: Until recently, no first-line targeted treatment options were available for patients with human epidermal growth factor receptor 2 (HER2)-mutant non-small-cell lung cancer (NSCLC). Zongertinib is an oral, irreversible tyrosine kinase inhibitor that selectively inhibits HER2 while sparing wild-type epidermal growth factor receptor (EGFR), thereby minimizing associated toxic effects.

METHODS: We conducted a phase 1a-1b, multicohort trial to assess zongertinib in patients with advanced or metastatic nonsquamous HER2-mutant NSCLC. Here, we evaluated zongertinib at a dose of 120 mg once daily in patients who had not previously received treatment (cohort 2). The primary end point was objective response as assessed by blinded independent central review. Secondary end points included duration of response and progression-free survival. In addition, zongertinib was evaluated in patients with active brain metastases (exploratory cohort 4).

RESULTS: In cohort 2, a total of 74 previously untreated patients received zongertinib at a dose of 120 mg. As of August 21, 2025, the percentage of patients with a confirmed objective response was 76% (95% confidence interval [CI], 65 to 84); the median duration of response was 15.2 months (95% CI, 9.8 to not evaluable), and the median progression-free survival was 14.4 months (95% CI, 11.1 to not evaluable). Adverse events of any grade occurred in 73 patients (99%), including events of grade 3 or higher in 33 patients (45%). Treatment-related adverse events occurred in 67 patients (91%), including events of grade 3 or higher in 14 patients (19%). In cohort 4, a total of 30 patients with active brain metastases received zongertinib at a dose of 120 mg; of these, 47% (95% CI, 30 to 64) had a confirmed intracranial objective response according to Response Assessment in Neuro-Oncology Brain Metastases criteria. In this cohort, treatment-related adverse events of grade 3 or higher occurred in 5 patients (17%).

CONCLUSIONS: Zongertinib showed sustained efficacy in previously untreated patients with advanced or metastatic HER2-mutant NSCLC. Treatment-related adverse events were predominantly low-grade. (Funded by Boehringer Ingelheim; Beamion LUNG-1 ClinicalTrials.gov number, NCT04886804.).

PMID: 41985129 [Indexed for MEDLINE]

3. BMJ. 2026 Apr 9;393:e085716. doi: 10.1136/bmj-2025-085716.

Efficacy and safety of VPM1002 and Immuvac in preventing tuberculosis: phase 3 randomised clinical trial (PreVenTB trial).

OBJECTIVE: To evaluate the safety and efficacy of VPM1002 and Immuvac in reducing the incidence of microbiologically confirmed tuberculosis (TB; pulmonary TB and extrapulmonary TB), development of latent TB infection, and immunogenicity.

DESIGN: Phase 3 randomised clinical trial (PreVenTB trial).

SETTING: 18 sites across six states of India.

PARTICIPANTS: 12 717 healthy household contacts (aged ≥6 years) of patients with a smear positive TB test.

INTERVENTIONS: Participants were randomly assigned in a 1:1:1 ratio (using block randomisation with variable sample size) to receive an intradermal injection of VPM1002, Immuvac, or placebo in both arms. After one month, a second dose was administered in one arm to 11 829 healthy participants.

OUTCOME MEASURES: The primary outcome was efficacy against confirmed TB (pulmonary TB and extrapulmonary TB) over 38 months of follow-up. Secondary outcomes were development of latent TB infection, adverse and serious adverse events, efficacy in predefined age groups, and immunogenicity. Exploratory outcomes were efficacy when considering tuberculin skin test status, and post hoc analyses of efficacy in participants aged 6-14 and according to body mass index.

RESULTS: 252 and 227 participants developed microbiologically confirmed TB in modified intention-to-treat and per protocol groups, respectively. The per protocol analysis showed 65 (1.68%), 80 (2.09%), and 82 (2.13%) participants developed TB in the VPM1002, Immuvac, and placebo groups, respectively. Of these, 12 (0.31%), 16 (0.42%), and 24 (0.62%) developed extrapulmonary TB in the VPM1002, Immuvac, and placebo groups, respectively. In the per protocol analysis, VPM1002 showed vaccine efficacy of 21.4% (95% confidence interval (CI) -8.9% to 43.2%), 19.5% (-14.6% to 43.4%), and 50.4% (0.8% to 75.2%) against all TB, pulmonary TB, and extrapulmonary TB, respectively. Immuvac showed vaccine efficacy of 33.2% (-25.9% to 64.5%) against extrapulmonary TB. VPM1002 and Immuvac showed vaccine efficacy of 64.9% (-2% to 90.1%) and 66.3% (1.9% to 90.5%) against extrapulmonary TB in participants with tuberculin skin test positivity. Both vaccines were well tolerated with mild local reactions in about a third of participants. VPM1002 and Immuvac induced Mycobacterium tuberculosis specific polyfunctional CD4+ T cells. Post hoc analyses showed vaccine efficacy of 64.6% (95% CI 16.3% to 85.1%) against all forms of TB, 62.1% (3.0% to 85.2%) against pulmonary TB, and 77.6% (-3.7% to 95.2%) against extrapulmonary TB in participants aged 6-14 years in the VPM1002 group.

CONCLUSIONS: Both vaccines were safe but did not show any efficacy against all forms of microbiologically confirmed TB or pulmonary TB. VPM1002 showed considerable efficacy against extrapulmonary TB. Both vaccines showed efficacy against extrapulmonary TB in participants who had a positive tuberculin skin test.

TRIAL REGISTRATION: Clinical Trials Registry India CTRI/2019/01/017026.

PMID: 41962942 [Indexed for MEDLINE]

4. N Engl J Med. 2026 Apr 30;394(17):1710-1722. doi: 10.1056/NEJMoa2509761.

Pulmonary Tuberculosis Detection with MiniDock MTB Using Swab Samples.

BACKGROUND: Improved diagnostic tools for tuberculosis that are suitable for use in peripheral health centers are essential for reducing the persistent gap between estimated and notified cases. The diagnostic accuracy and usability of the MiniDock MTB test for detecting pulmonary tuberculosis is unknown.

METHODS: We conducted a prospective, cross-sectional study at outpatient centers in India, Nigeria, the Philippines, South Africa, Uganda, Vietnam, and Zambia. Patients 12 years of age or older with presumptive pulmonary tuberculosis were enrolled between September 12, 2024, and March 31, 2025. Assessment with MiniDock MTB was performed with sputum swabs and tongue swabs. Diagnostic accuracy was evaluated against a sputum-culture-based reference and as compared with sputum-smear microscopy and Xpert MTB/RIF Ultra assay. Usability was assessed with a system usability scale and direct observation.

RESULTS: A total of 1380 participants were enrolled; 255 (18.5%) had human immunodeficiency virus infection and 226 (16.4%) had culture-confirmed tuberculosis. MiniDock MTB sensitivity was 85.7% (95% confidence interval [CI], 80.4 to 90.0) with sputum and 79.6% (95% CI, 73.8 to 84.7) with tongue swabs; specificity was greater than 97.5% for both. Results of sputum tests with MiniDock MTB closely matched those with Xpert MTB/RIF Ultra for sensitivity (difference, -2.8 percentage points; 95% CI, -6.0 to 0.5). MiniDock MTB had greater sensitivity than smear microscopy for tests of sputum (difference, 24.3 percentage points; 95% CI, 17.9 to 30.7) and tongue swabs (difference, 18.3 percentage points; 95% CI, 12.0 to 24.7). The test showed diagnostic accuracy that was consistent with World Health Organization (WHO) accuracy targets for near-point-of-care tuberculosis diagnostics (≥85% sensitivity for sputum and ≥75% for nonsputum and ≥98% specificity for both). The median score on the system usability scale (range, 0 to 100, with higher scores indicating better perceived usability) was 75 (interquartile range, 65 to 80), which indicated good usability. No adverse events related to the index test were reported.

CONCLUSIONS: MiniDock MTB met WHO targets for diagnostic accuracy and usability for tuberculosis detection across diverse clinical settings. (Funded by the National Institutes of Health and others; Rapid Research in Diagnostics Development for TB Network and Assessing Diagnostics at Point-of-Care for Tuberculosis ClinicalTrials.gov numbers, NCT04923958 and NCT05941052.).

PMID: 42054680 [Indexed for MEDLINE]

5. Cancer Cell. 2026 Apr 23:S1535-6108(26)00172-8. doi: 10.1016/j.ccell.2026.03.018. Online ahead of print.

JYP0322, a highly selective and brain-penetrant ROS1 inhibitor, overcomes ROS1(G2032R) resistance mutation in NSCLC: The first-in-human phase 1 trial.

Targeted therapies against ROS1-rearrangements face limitations due to resistance mutations, brain metastases, and central nervous system toxicities. We have developed a next-generation, brain-penetrant ROS1 inhibitor, JYP0322, that can overcome resistance mutations (e.g., ROS1G2032R) while minimizing off-target inhibition. In preclinical studies, JYP0322 demonstrated >130-fold selectivity over TRKA, potent antitumor activity in ROS1 re-arrangement and ROS1G2032R tumor models, and effective brain penetration (CSF/plasma AUC ratio 0.893). In a phase I trial (NCT06128148) enrolling 89 non-small cell lung cancer (NSCLC) patients with ROS1-fusion (36% with brain metastases), JYP0322 was well tolerated with low TRK-related neurologic events (dizziness: 6.7%; headache: 3.4%). Among 80 efficacy-evaluable patients, the objective response rate (ORR) was 95.7% in TKI-naive, 57.1% in those with ≥2 prior TKIs, and 77.8% in ROS1G2032R-mutant patients. Intracranial ORR was 55.6% among brain-metastatic patients. These findings highlight JYP0322 as a promising therapy for heavily pretreated NSCLC patients, including those with brain metastases or ROS1G2032R mutations.

PMID: 42030931

6. Cancer Discov. 2026 Apr 22. doi: 10.1158/2159-8290.CD-25-1454. Online ahead of print.

BLOCKADE OF TUMOR-INTRINSIC TGF-Β SIGNALING DRIVES HYPERPROGRESSION IN SMALL CELL LUNG CANCER.

Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but their tumor-intrinsic consequences remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGF-β inhibitor, in small cell lung cancer. Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n=450), in higher frequencies with bintrafusp than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGF-β signaling. Functional studies demonstrated that tumor-intrinsic TGF-β signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGF-β-high transcriptional state associated with inferior survival. Together, these findings identify a context-dependent, growth-constraining function of TGF-β and support tumor-intrinsic biomarker-guidance while targeting stromal immunosuppressive pathways.

PMID: 42018154

7. J Clin Oncol. 2026 Apr 21:JCO2600434. doi: 10.1200/JCO-26-00434. Online ahead of print.

Long-Term Efficacy and Safety of Taletrectinib in Patients With ROS1+ Non-Small Cell Lung Cancer: Results From the Phase II TRUST-I Study.

Taletrectinib is a next-generation, CNS-active, selective ROS1 tyrosine kinase inhibitor (TKI) with activity against the ROS1 G2032R resistance mutation. Initial data from the TRUST-I study (ClinicalTrials.gov identifier: NCT04395677) demonstrated high response rates and intracranial (IC) activity, with promising durability, in Chinese patients with advanced ROS1+ non-small cell lung cancer (NSCLC). With longer follow-up, taletrectinib continued to demonstrate high and durable response rates in both TKI-naïve and crizotinib-pretreated patients, including IC activity and promising overall survival (OS). Among 103 TKI-naïve patients who started taletrectinib at 600 mg once daily (median follow-up, 51.0 months), the objective response rate (ORR) was 90.3% (95% CI, 82.9 to 95.3), the median duration of response (DOR) and median progression-free survival (PFS) exceeded 4 years (49.7 months and 49.6 months, respectively), and median OS was not reached. Among 66 crizotinib-pretreated patients (median follow-up, 45.2 months), the ORR was 51.5%, the median DOR was 13.2 months, the median PFS was 7.6 months, and the median OS was 25.6 months. The safety profile remained consistent with prior reports, and no new safety signals were identified. Overall, taletrectinib demonstrated durable long-term efficacy and a manageable safety profile in patients with advanced ROS1+ NSCLC.

PMID: 42013573

8. J Clin Oncol. 2026 Apr 21:JCO2502187. doi: 10.1200/JCO-25-02187. Online ahead of print.

Amivantamab Monotherapy in Chemorefractory RAS/BRAF Wild-Type Metastatic Colorectal Cancer: Results From OrigAMI-1, an Open-Label, Phase Ib/II Study.

PURPOSE: Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, is approved in non-small cell lung cancer (NSCLC). Effective treatments are limited for chemorefractory metastatic colorectal cancer (mCRC).

METHODS: OrigAMI-1 (ClinicalTrials.gov identifier: NCT05379595) is a phase Ib/II study evaluating amivantamab monotherapy in chemorefractory (2-3 prior lines) mCRC. Participants had centrally confirmed RAS/BRAF/EGFR ectodomain wild-type status, without ERBB2/HER2 amplification. Participants with left-sided mCRC without (cohort A) or with (cohort B) prior anti-EGFR antibody treatment, or right-sided mCRC (cohort C) regardless of prior anti-EGFR treatment, received intravenous amivantamab 1,050 mg (1,400 mg for ≥80 kg) once every 2 weeks. The primary end point was objective response rate (ORR) per RECIST v1.1.

RESULTS: By October 31, 2024, 94 participants received amivantamab monotherapy (median follow-up, 11.9 months). The median age was 60 years, and 65% of participants were male, with a median of 2 prior lines (94%, prior bevacizumab). In left-sided cohorts, the ORR was 29% (5 of 17) in cohort A and 19% (10 of 54) in cohort B; the median duration of response (DoR) was 9.0 months and 6.1 months, and the median progression-free survival (PFS) was 5.7 months and 4.6 months, respectively. In the right-sided cohort, the ORR was 22% (10 of 23; 43% had prior anti-EGFR), the median DoR was 9.8 months, and the median PFS was 3.7 months. Most frequent treatment-related grade ≥3 adverse events (AEs) were rash (7%), dermatitis acneiform (4%), and hypoalbuminemia (4%). One participant discontinued amivantamab because of a treatment-related AE.

CONCLUSION: Amivantamab monotherapy demonstrated promising, durable antitumor activity in chemorefractory mCRC, regardless of prior anti-EGFR therapy and the primary tumor location. The amivantamab safety profile in mCRC is consistent with experience in NSCLC. Amivantamab plus chemotherapy is currently being explored in two phase III studies in first-line and second-line mCRCs.

PMID: 42013403

9. Cancer Discov. 2026 Apr 20:OF1-OF20. doi: 10.1158/2159-8290.CD-25-0470. Online ahead of print.

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

10. J Clin Oncol. 2026 Apr 20:JCO2502016. doi: 10.1200/JCO-25-02016. Online ahead of print.

First-in-Human, Phase I Study of Sigvotatug Vedotin, an Integrin Beta-6-Directed Antibody-Drug Conjugate: Results From Dose Expansion in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Integrin beta-6 (IB6) is highly expressed in non-small cell lung cancer (NSCLC) and other solid tumors and potentially associated with poor outcomes. Sigvotatug vedotin (SV), a novel IB6-directed antibody-drug conjugate, demonstrated acceptable safety and encouraging antitumor activity in dose escalation. We report updated results for dose-expansion regimens in advanced NSCLC (aNSCLC).

METHODS: SGNB6A-001 is an open-label, multicenter, dose-escalation/dose-expansion phase I study evaluating safety, tolerability, pharmacokinetics (PK), and antitumor activity of SV in patients with select advanced solid tumors. After dose escalation, dose expansion further explored three regimens: 1.25 mg/kg total body weight (TBW) on Days 1 and 8 of a 21-day cycle, 1.5 mg/kg TBW on Days 1 and 15 of a 28-day cycle (once every 2 weeks), and 1.8 mg/kg adjusted ideal body weight (AiBW) once every 2 weeks. Eligible patients had prior chemotherapy and immunotherapy or targeted therapy if indicated. Primary end points were safety and determination of an optimal dosing schedule. Secondary end points were antitumor activity, PK, and immunogenicity.

RESULTS: As of November 26, 2024, 117 patients with aNSCLC were treated in the above cohorts. Any-grade and grade ≥3 treatment-emergent adverse events occurred in 98% and 48% of all patients, respectively, and in 94% and 35% of patients receiving SV 1.8 mg/kg AiBW once every 2 weeks. Modeling revealed that the AiBW regimen resulted in lower PK variability than TBW regimens. The objective response rate and median duration of response were 19% and 11.3 months in the overall population, respectively, and 29% and 12.8 months in patients with nonsquamous, taxane-naïve NSCLC.

CONCLUSION: SV demonstrated a manageable safety profile and promising antitumor activity with durable responses in aNSCLC. PK and clinical data support further investigation with the recommended 1.8-mg/kg AiBW once every 2 weeks dosing regimen.

PMID: 42008777

11. Lancet Infect Dis. 2026 Apr 20:S1473-3099(26)00114-3. doi:10.1016/S1473-3099(26)00 114-3. Online ahead of print.

Diagnostic and prognostic accuracy of the Mycobacterium tuberculosis host response 3-gene cartridge among tuberculosis household contacts in Mozambique, Tanzania, and Zimbabwe: a prospective, longitudinal, diagnostic and prognostic accuracy cohort study.

BACKGROUND: Tuberculosis elimination is constrained by symptom-based and sputum-dependent diagnostic strategies, which miss asymptomatic disease and are difficult to deploy in community settings. Household contacts of people with tuberculosis are a priority population for screening and preventive therapy, but existing tests have poor prognostic ability. We aimed to evaluated host-response assays for screening and prognostic use in household contacts of people with tuberculosis.

METHODS: In this prospective, longitudinal, diagnostic and prognostic accuracy study, we recruited people aged 10 years and older who lived with a person diagnosed with tuberculosis in Mozambique, Tanzania, or Zimbabwe. Household contacts who had taken antimycobacterial antibiotics within the past 4 weeks were excluded. Participants had real-time Cepheid Xpert Mycobacterium tuberculosis Host Response (MTB-HR) testing and clinical, radiological, and microbiological tuberculosis screening every 6 months for up to 24 months. The primary outcomes were the diagnostic accuracy of MTB-HR obtained within 30 days of a confirmed or likely tuberculosis diagnosis at any baseline or follow-up visit, and the prognostic ability of MTB-HR for incident tuberculosis using MTB-HR results obtained 1-6 months, 6-12 months, and 1-12 months before incident tuberculosis diagnosis. Tuberculosis diagnoses were established by an endpoint review committee and we assessed discrimination using the area under the receiver operating characteristic (AUROC) curve. The study was registered with ClinicalTrials.gov (NCT04781257) and is completed.

FINDINGS: Between March 8, 2021, and March 23, 2023, we screened 2109 household contacts and enrolled 2079 for analysis (1294 [62·2%] female and 785 [37·8%] male). In the diagnostic analysis (41 household contacts with tuberculosis), the AUROC was 0·86 (95% CI 0·79-0·92). The prognostic analysis included 29 people with incident tuberculosis during the 1-6-month interval, 19 people for the 6-12-month interval, and 39 people for the 1-12-month interval, yielding AUROCs of 0·80 (0·71-0·89), 0·64 (0·53-0·76), and 0·71 (0·62-0·79), respectively, at optimised cutoffs. For the 6-month prediction at the optimised cutoff, the positive predictive value was 7·5% (95% CI 4·9-11·4).

INTERPRETATION: MTB-HR did not meet the 2025 WHO target product profile criteria for screening or prognostic use; however, its positive predictive value for incident tuberculosis was higher than that of currently used tests. These findings support a potential role for MTB-HR in screening and prevention strategies.

FUNDING: The second European and Developing Countries Clinical Trials Partnership (EDCTP2) programme.

PMID: 42026013

12. Clin Microbiol Rev. 2026 Apr 20:e0035325. doi: 10.1128/cmr.00353-25. Online ahead of print.

Management of latent tuberculosis infection in patients with kidney disease.

SUMMARY Latent tuberculosis infection (LTBI) is common and preventable among patients with chronic kidney disease (CKD), where uremia and iatrogenic immunosuppression heighten reactivation risk. This narrative review synthesizes evidence across pre-dialysis CKD, dialysis, and kidney transplantation to propose a pragmatic care pathway. In advanced CKD, the tuberculin skin test performs poorly, whereas interferon-γ release assays (IGRAs) are preferred. Screening should be risk-targeted in pre-dialysis CKD, systematic at dialysis initiation, and mandatory pre-transplant for candidates and living donors. Following a positive test, clinicians must exclude active tuberculosis via clinical assessment and chest imaging before starting preventive therapy. Short-course rifamycin-based regimens (4 months of daily rifampin [4R], 3 months of once‑weekly isoniazid plus rifapentine [3HP], or 3 months of daily isoniazid plus rifampin [3HR]) enhance completion rates compared with 9 months of daily isoniazid (9H). In transplant recipients, rifamycin interactions with calcineurin and Mammalian target of rapamycin (mTOR) inhibitors typically favor 9H; rifamycins demand expert multidisciplinary management with intensive therapeutic drug monitoring. Programmatic data from dialysis units show high completion with tolerable toxicity, affirming routine feasibility. We integrate IGRA-based screening at critical transitions with tailored regimen selection, pyridoxine coadministration for isoniazid, and structured safety monitoring. Priorities include validating novel Mycobacterium tuberculosis antigen-based skin tests in CKD and developing implementation strategies to standardize renal care. We delineate setting-specific approaches for high- versus low-burden countries, addressing subclinical and incipient TB challenges in high-burden contexts. Adopting this framework can curb active TB progression, safeguard grafts, and enhance patient outcomes.

PMID: 42007724

13. Sci Transl Med. 2026 Apr 15;18(845):eads8681. doi: 10.1126/scitranslmed.ads8681. Epub 2026 Apr 15.

The orphan receptor GPR84 drives inflammation in Buruliulcer development.

Inflammatory responses can be of critical importance in determining both the course and outcome of infectious diseases. Buruli ulcer, a neglected tropical disease caused by Mycobacterium ulcerans (M. ulcerans), has been reported to induce both immunosuppressive and proinflammatory responses in the skin. Here, we found that genetic inactivation of the orphan receptor GPR84 in mice leads to spontaneous healing of ulcerative lesions, recapitulating the rare spontaneous healing observed in human Buruli ulcer. Mechanistically, M. ulcerans infection induced Gpr84 expression through Toll-like receptor 2 engagement, promoting proinflammatory cytokine release through a self-amplifying loop that sustained receptor expression and inflammatory signaling. Moreover, pharmacological inhibition of GPR84 with the antagonist PBI-4050, in combination with antibiotics, accelerated tissue repair in infected GPR84-competent mice, which was associated with attenuation of inflammatory responses. Together, these findings establish GPR84 as a promising target for host-directed therapeutic interventions in Buruli ulcer and its expression as a potential biomarker of lesion activity.

PMID: 41984933 [Indexed for MEDLINE]

14. Nat Microbiol. 2026 Apr 3. doi: 10.1038/s41564-026-02317-3. Online ahead of print.

Lipid accumulation in tuberculosis granulomas inhibits macrophage-CD4(+) T cell interactions and infection control.

Granulomas form to contain Mycobacterium tuberculosis (Mtb) infection in the lung. What constitutes protective or detrimental responses is poorly understood. Here, using spatial transcriptomics and immunofluorescence microscopy of human lung samples and mouse models, we characterize the spatial structure and transcriptome of macrophage and T cell populations in tuberculosis granulomas. We identify signatures of reduced major histocompatibility complex (MHC) class II levels on macrophages and reduced CD4+ T cell activation, particularly in necrotic granulomas, suggesting a compromised interaction between innate and adaptive responses. Further analyses in mouse models and human cells reveal that infection of macrophages, or exposure to mycolic acids, disrupt cholesterol trafficking, leading to cholesterol accumulation and MHC class II sequestration in lysosomes. This inhibits antigen presentation and impairs anti-Mtb CD4+ T cell responses. Pharmacological restoration of cholesterol homeostasis during late-stage infection improves control of Mtb in mice. This study reveals an infection-driven mechanism of cholesterol overload, which impairs control of tuberculosis and could be targeted therapeutically.

PMID: 41933199

15. Sci Adv. 2026 Apr 3;12(14):eaec5100. doi: 10.1126/sciadv.aec5100. Epub 2026 Apr 1.

A periplasmic protein complex mediates arabinofuranosyltransferase activity and intrinsic drug resistance in Mycobacterium tuberculosis.

The intrinsic drug resistance of Mycobacterium tuberculosis (Mtb) is a major barrier to effective tuberculosis (TB) treatment and is largely due to its complex, impermeable cell envelope. We identified a periplasmic protein complex comprising FecB and Rv3035 that is essential for maintaining envelope integrity and mediating intrinsic multidrug resistance in Mtb. FecB interacts with Rv3035, forming a stable heterodimer that associates with the cell envelope biosynthesis protein AftB. We report the structures of Rv3035 alone and in complex with FecB and identify critical residues for complex formation and function. Coessentiality and genetic interaction analyses support a functional link between FecB, Rv3035, and AftB, an arabinofuranosyltransferase that synthesizes arabinogalactan and lipoarabinomannan. Loss of FecB or Rv3035 disrupted AftB-mediated arabinan synthesis, suggesting that these proteins support AftB's enzymatic activity. FecB is required for Mtb virulence in mice, underscoring its physiological relevance. These findings highlight FecB, Rv3035, and AftB as promising therapeutic targets.

PMID: 41920993 [Indexed for MEDLINE]

16. Nat Immunol. 2026 Apr; 27(4):867-880. doi: 10.1038/s41590-026-02431-8.  Epub 2026 Feb 23.

The immunometabolic topography of cellular organization and bacterial control in tuberculosis granulomas.

Despite being heavily infiltrated by immune cells, tuberculosis (TB) granulomas often subvert the host response to Mycobacterium tuberculosis (Mtb) infection and support bacterial persistence. Human TB granulomas are enriched for immunosuppressive factors typically associated with tumor-immune evasion, raising the possibility that they promote tolerance to infection. Here we identify candidate drivers for establishing this tolerogenic niche and show that the magnitude of this response correlates with bacterial persistence. We conducted a multimodal spatial analysis of 52 granulomas from 16 nonhuman primates infected with low-dose Mtb for 9-12 weeks. Each granuloma's bacterial burden was quantified individually, enabling us to assess how granuloma spatial structure and function relate to infection control. We found that a universal feature of TB granulomas is partitioning of the myeloid core into two distinct metabolic environments, one of which is hypoxic. This hypoxic environment is associated with pathological immune cell states, dysfunctional cellular organization of the granuloma, and a near-complete blockade of lymphocyte infiltration that would be required for a successful host response. The extent of these hypoxia-associated features correlates with higher bacterial burden. We conclude that hypoxia correlates with immune cell state and organization within granulomas and might subvert immunity to TB.

PMID: 41731147 [Indexed for MEDLINE]

17. Lancet Glob Health. 2026 May;14(5):e817-e828. doi: 10.1016/S2214-109X(25)00540-6. Epub 2026 Apr 15.

Untangling the complex relationship between HIV-exposure and tuberculosis in children: a narrative review.

With the remarkable success of antiretroviral programmes for the prevention of vertical HIV transmission, there has been a notable reduction in the proportion of children born with HIV and, subsequently, a corresponding increase in the population of children who are HIV-exposed but uninfected (CHEU). There is growing appreciation for the increased risk of childhood morbidity and mortality among CHEU compared with children who are HIV-unexposed, particularly from infectious diseases. Given the high prevalence of tuberculosis in populations with high HIV prevalence, the effect of HIV exposure on tuberculosis is therefore of particular interest. In this Review, we contextualise and reflect on the existing literature for CHEU with regard to prevention, prevalence, and outcomes of tuberculosis infection and tuberculosis disease. In so doing, we identify gaps in reported knowledge on CHEU to guide future research.

PMID: 41999718 [Indexed for MEDLINE]

18. Cancer Discov. 2026 Apr 19. doi: 10.1158/2159-8290.CD-25-2318. Online ahead of print.

A Roadmap to Transform Lung Cancer Outcomes: Priorities in Biology, Therapeutic Innovation, Early Detection, Prevention and Interception.

Advances in targeted therapies, immunotherapy, and early detection have revolutionized lung cancer treatment and extended survival. Nonetheless, lung cancer remains highly fatal. Here, we identify knowledge gaps and propose critical areas of future research, aligning with the mission of the AACR Lung Cancer Task Force. We delineate research priorities, including advancing prevention initiatives, enhancing early detection strategies, developing novel treatments, and refining patient stratification. Addressing disparities and increasing efforts on relatively neglected lung cancer subtypes are also essential. Finally, international collaboration, centralized clinical trial databases, novel clinical trial designs, and artificial intelligence-driven analytics should accelerate precision medicine and aid in elucidating drug resistance mechanisms. Together, these efforts promise to improve patient outcomes.

PMID: 42001483

19. Cancer Cell. 2026 Apr 17:S1535-6108(26)00171-6. doi: 10.1016/j.ccell.2026.03.017. Online ahead of print.

Efficacy, safety, and biomarker analysis of datopotamab deruxtecan in advanced non-small cell lung cancer: ICARUS-LUNG01 phase 2 study.

Antibody-drug conjugates (ADCs) are rapidly transforming the treatment landscape of advanced non-small cell lung cancer (NSCLC), yet validated predictive biomarkers to guide their use remain lacking. ICARUS-LUNG01 is a prospective, phase II study designed to integrate clinical outcomes with longitudinal translational analyses. In this multicenter trial, 100 pretreated patients with advanced NSCLC received the TROP2-directed ADC datopotamab deruxtecan (Dato-DXd). The study reported an objective response rate (ORR) of 26.0%, with a median progression-free survival (PFS) of 3.6 months, and a greater benefit observed in non-squamous tumors. Baseline and on-treatment tumor analyses suggested that resistance to Dato-DXd could be associated with a lack of TROP2 cytoplasmic staining and the early activation of DNA repair pathways. Conversely, the activation of immune-related pathways was associated with treatment response. Validation of these findings in phase III studies will be essential to define biomarkers, ultimately enabling more precise identification of patients most likely to benefit from Dato-DXd.

PMID: 41999747

20. J Clin Oncol. 2026 Apr 17:JCO2502375. doi: 10.1200/JCO-25-02375. Online ahead of print.

Selpercatinib and the Crossover Conundrum: Potential Impact of Postprogression Therapies on Overall Survival.

Overall survival (OS) should be evaluated in all randomized cancer trials, even when not the primary end point, as it is clinically meaningful and measures both safety and efficacy. Crossover from the control to experimental arms in randomized trials may be incorporated to allow access to promising investigational treatments after progression on a control arm. The results of Study LIBRETTO-431, an ex-US multiregional, open-label, randomized, active-controlled trial of selpercatinib versus platinum-based and pemetrexed chemotherapy with or without pembrolizumab in patients with treatment-naïve advanced rearranged during transfection fusion-positive non-small cell lung cancer, highlight the challenges of interpreting OS in trials with high crossover rates and variable postprogression therapies. Trial results demonstrated a large improvement in progression-free survival with an acceptable safety profile, but were accompanied by an immature OS analysis with a hazard ratio of 1.26, favoring the chemoimmunotherapy arm. Regardless of the position of OS in the end point hierarchy, it is critical that OS analyses include prespecified plans for data collection and analytical methods to account for the potential impact of postprogression therapies on the interpretation of study results.

PMID: 41996652

21. JAMA Oncol. 2026 Apr 9:e260669. doi: 10.1001/jamaoncol.2026.0669. Online ahead of print.

Outcomes and Treatments of Patients With Non-Small Cell Lung Cancer Who Received Pembrolizumab.

IMPORTANCE: Two years of immunotherapy is the standard treatment for most patients with advanced non-small cell lung cancer. However, little is known about postimmunotherapy therapeutic strategies.

OBJECTIVE: To describe subsequent treatments and outcomes after pembrolizumab discontinuation following 2 years of therapy.

DESIGN, SETTING, AND PARTICIPANTS: This nationwide, population-based, retrospective cohort study used administrative health data from the French National Health Insurance database from patients who received a diagnosis of incident lung cancer between January 1, 2015, and December 31, 2022, who received pembrolizumab for 22 to 26 months and survived at least 29 months (landmark). The data cutoff was October 31, 2024. Data were analyzed in October 2025.

EXPOSURE: Treatment with pembrolizumab for 22 to 26 months, followed by observation of subsequent therapeutic management after discontinuation.

MAIN OUTCOMES AND MEASURES: Overall survival (OS) was defined as the time between landmark and death of any cause. Time to next treatment or death was defined as the time between the last pembrolizumab infusion and new treatment or death.

RESULTS: Among 41 498 patients who received frontline pembrolizumab for advanced disease, 5293 were alive at the landmark time and completed 2 years of treatment, and 1555 discontinued pembrolizumab at 2 years. The population of interest for this study included 1480 patients with at least 6 months of follow-up; the median (range) age was 63.0 (32.0-90.0) years, 537 (36.3%) were female, 943 (63.7%) were male, and 616 (41.6%) had received pembrolizumab monotherapy. After a median follow-up of 16 months (95% CI, 15.2-16.8) after the landmark, the OS rate at 48 months was 76.9% (95% CI, 72.7%-81.3%), and the time to next treatment or death rate at 48 months after pembrolizumab discontinuation was 49.9% (95% CI, 45.3%-55.0%). Overall, 387 patients (26.1%) received subsequent therapy. The first treatments after pembrolizumab discontinuation were chemotherapy (200 [51.7%]), radiotherapy (183 [47.3%]), and immunotherapy (4 [1.0%]). Considering all subsequent treatment lines, 19 patients (0.1%) received an immunotherapy rechallenge. Twelve months after initiation of the new treatment, the OS rates were 87.0% (95% CI, 81.6%-92.7%) for radiotherapy, 69.9% (95% CI, 61.1%-80.0%) for chemotherapy, and 61.4% (95% CI, 41.3%-91.4%) for immunotherapy.

CONCLUSIONS: This cohort study found that, among long-term cancer survivors with advanced non-small cell lung cancer who were treated with pembrolizumab, survival outcomes were high and immunotherapy rechallenge was uncommon.

PMID: 41954917

22. Lancet Oncol. 2026 Apr;27(4):432-441. doi: 10.1016/S1470-2045(25)00764-8.

Fulzerasib plus cetuximab in first-line KRAS(G12C)-mutated non-small-cell lung cancer (KROCUS): a single-arm, multicentre, phase 1b/2 trial.

BACKGROUND: Fulzerasib, a KRASG12C inhibitor, has shown clinical activity in previously treated non-small-cell lung cancer (NSCLC). Clinical studies indicate that combining a KRASG12C inhibitor with an anti-EGFR antibody is effective in colorectal cancer; however, its benefit in NSCLC remains to be explored.

METHODS: This single-arm, phase 1b/2 trial enrolled patients at 30 medical centres in Spain, Italy, and Greece. Eligible patients had KRASG12C-mutated NSCLC with no previous systemic anti-tumour therapy for advanced or metastatic disease and were aged 18 years and older; had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1; had an Eastern Cooperative Oncology Group performance status of 0 or 1; and had a life expectancy of 3 months or more. Enrolled patients received 600 mg oral fulzerasib twice daily plus 500 mg/m2 intravenous cetuximab every 2 weeks. The primary endpoint was investigator-assessed objective response rate per

RECIST 1.1 assessed in the full response analysis set. The study was registered with ClinicalTrials.gov (NCT05756153) and is complete.

FINDINGS: Between April 23, 2023, and April 15, 2024, a total of 60 patients were screened, and 47 patients (78%) received treatment. The median age was 68 years (IQR 59-72); 25 patients (53%) were male and 22 (47%) were female. 45 (95%) patients were current or former smokers. As of Jan 14, 2025, the median follow-up time and treatment duration were 12·8 months (90% CI 11·6-14·6) and 10·1 months (IQR 6·3-13·0) months, respectively. The confirmed objective response rate was 69% (90% CI 56-80). Treatment-related adverse events (TRAEs) occurred in 41 (87%) of the 47 patients (grade 3 in seven [15%]). No grade 4 or 5 TRAEs were observed. TRAEs led to drug discontinuation in three (6%) patients, with only cetuximab being discontinued.

INTERPRETATION: In treatment-naive KRASG12C-mutated NSCLC, fulzerasib plus cetuximab showed encouraging activity with a favourable safety profile. The combination is currently being planned for investigation in a phase 3 study.

PMID: 41926959 [Indexed for MEDLINE]

23. Nat Immunol. 2026 Apr;27(4):715-724. doi: 10.1038/s41590-026-02445-2.  Epub 2026 Mar 23.

Chemokine-defined macrophage niches establish spatial organization of tumor immunity.

Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206hi and CD206lo interstitial macrophage (IM) subsets and Ly6c2+Fn1+Vcan+ recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identified chemokine-expressing IM subsets with opposing functions. Cxcl13+CD206hi IMs, Cxcl9+CD206hi IMs and Cxcl10+CD206hi IMs positioned along bronchovascular regions drove tertiary lymphoid structure formation, lymphocyte recruitment and tumor control, whereas Ccl2+ IMs, localized within tumor regions, recruited protumorigenic Ly6c2+Fn1+Vcan+ recMacs. In addition, Ly6C+CD11b+ monocyte-derived dendritic cells (moDCs) functioned as immunosuppressive antigen-presenting cells in tumor-draining lymph nodes. During neoantigen vaccination, CCR5 blockade with maraviroc selectively inhibited antigen-bearing moDC migration, enhancing dendritic cell-mediated antitumor immunity. These findings showed how macrophage lineage and spatial compartmentalization govern tumor immunity and identified strategies to preserve protective IM functions, while disrupting macrophage-driven immunosuppression.

PMID: 41872505 [Indexed for MEDLINE]

24. Nature. 2026 Apr;652(8111):995-1003. doi: 10.1038/s41586-026-10243-x. Epub 2026 Mar

Thymic health and immunotherapy outcomes in patients with cancer.

Although immunotherapy has revolutionized cancer treatment, many patients still experience limited benefit, highlighting the urgent need for improved biomarkers1. Although immunotherapy is founded on unleashing T cells2, most existing biomarkers remain tumour-centric and mainly overlook host immune competence. The thymus is a key immune organ that is crucial for T cell maturation, and we hypothesized that thymic functionality is associated with immunotherapy outcomes3. Here we show that thymic health, a radiographic measure of thymic functionality, is strongly associated with immunotherapy outcomes across several cancer types. Using a deep-learning framework applied to routine computed tomography images, we quantified thymic health in a pan-cancer cohort of 3,476 patients receiving immune checkpoint inhibitors. In patients with non-small cell lung cancer, higher thymic health was associated with reduced risks of progression and all-cause mortality. These associations remained significant across clinically relevant levels of programmed death ligand 1 (PD-L1) and tumour mutation burden. In the prospective TRACERx lung cancer study, thymic health was positively associated with T cell receptor diversity and T cell receptor excision circles, and correlated with immune-system signalling pathways, supporting radiographic thymic health as a proxy for thymic activity and adaptive immune competence. Analysis across patients with melanoma, breast cancer or renal cancer demonstrated pan-cancer relevance. Together, these findings identify thymic health as a previously unrecognized, tumour-agnostic determinant of immunotherapy efficacy, with potential implications for patient stratification, treatment timing and the development of immune-rejuvenating strategies in precision immuno-oncology.

PMID: 41851467 [Indexed for MEDLINE]

25. Lancet Oncol. 2026 Apr;27(4):419-431. doi: 10.1016/S1470-2045(26)00049-5. Epub 2026 Mar 10.

Benmelstobart plus anlotinib versus pembrolizumab as first-line treatment for PD-L1-positive, advanced non-small-cell lung cancer (CAMPASS): a blinded, randomised, controlled, phase 3 trial.

BACKGROUND: PD-1 and PD-L1 inhibitors have been shown to synergise with anti-angiogenic agents in non-small-cell lung cancer (NSCLC). We aimed to compare benmelstobart plus anlotinib with pembrolizumab in patients with previously untreated, driver gene-negative, PD-L1-positive, advanced NSCLC.

METHODS: The blinded, randomised, controlled, phase 3 CAMPASS trial was conducted in 79 centres across China. Patients aged 18-75 years with stage IIIB-IV squamous or non-squamous NSCLC, no previous systemic treatment for advanced, recurrent or metastatic diseases, a PD-L1 tumour proportion score of 1% or greater, a life expectancy of 3 months or longer, at least one measurable lesion, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (2:1) to receive intravenous benmelstobart (1200 mg once on day 1) plus oral anlotinib (12 mg daily on days 1-14) or intravenous pembrolizumab (200 mg once on day 1) plus placebo every 3 weeks. Randomisation was done centrally and stratified by tumour histology, PD-L1 tumour proportion score, and brain metastases. Treatment allocation was open label for investigators and masked to patients and statisticians. The primary endpoint was progression-free survival as assessed by a blinded independent review committee per Response Evalutation Criteria in Solid Tumours version 1.1 in the intention-to-treat population (all randomly assigned patients). Safety was assessed in all randomly assigned patients who received at least dose of study drug. Results reported here are from a preplanned final analysis for progression-free survival. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT04964479.

FINDINGS: Between Aug 6, 2021, and Dec 14, 2022, 531 patients were randomly assigned (354 to the benmelstobart plus anlotinib group and 177 to the pembrolizumab plus placebo group). 449 (85%) patients were male, 82 (15%) were female, and 493 (93%) were of Han ethnicity. Two patients in the benmelstobart plus anlotinib group and one patients in the pembrolizumab plus placebo group were untreated and therefore excluded from the safety population. After a median follow-up of 11·4 months (95% CI 9·4-13·1) for the benmelstobart plus anlotinib group and 10·6 months (9·0-13·0) for the pembrolizumab plus placebo group, median progression-free survival was 11·0 months (9·2-12·6) and 7·1 months (5·8-9·5), respectively (hazard ratio [HR] 0·70 [95% CI 0·54-0·90]; log-rank p=0·0057). Grade 3 or worse treatment-related adverse events occurred in 206 (59%) of 352 patients in the benmelstobart plus anlotinib group and 51 (29%) of 176 patients in the pembrolizumab plus placebo group, and the most frequent one was hypertension (90 [26%] vs five [3%]). Serious treatment-related adverse events occurred in 89 (25%) patients in the benmelstobart plus anlotinib group and 37 (21%) patients in the pembrolizumab plus placebo group, the most common of which were haemoptysis (nine [3%] vs none) and immune-mediated pulmonary diseases (eight [2%] vs five [3%]). Five (1%) treatment-related deaths occurred in the benmelstobart plus anlotinib group (two due to haemoptysis and one each due to immune-mediated pulmonary disease, disease progression, and infection pneumonia) and four (2%) occurred in the pembrolizumab plus placebo group (one each due to respiratory failure, pulmonary inflammation, disease progression, and myocardial injury).

INTERPRETATION: Benmelstobart plus anlotinib showed longer progression-free survival than pembrolizumab plus placebo and no unexpected safety signals were reported, suggesting benmelstobart plus anlotinib as a potential first-line option in driver gene-negative, PD-L1-positive, advanced NSCLC. Longer term follow-up is needed to establish effects on overall survival.

PMID: 41825453 [Indexed for MEDLINE]

26. Nature. 2026 Apr;652(8112):1339-1348. doi: 10.1038/s41586-026-10216-0. Epub 2026 Mar 11.

Ageing promotes metastasis via activation of the integrated stress response.

Lung cancer predominantly affects older individuals, yet how physiological ageing influences tumour evolution remains poorly understood1. Here we show that ageing reprograms the evolutionary trajectory of KRAS-driven lung adenocarcinoma, limiting primary tumour growth while promoting metastatic dissemination through epigenetic activation of the integrated stress response (ISR). The ISR effector ATF4 drives epithelial and metabolic plasticity, conferring metastatic competence. Mechanistically, aged tumour cells show increased sensitivity to the PERK-eIF2α arm of the unfolded protein response, sustaining persistent ATF4 signalling. Targeting ISR-ATF4 genetically or pharmacologically abolishes these adaptations and limits dissemination, whereas ATF4 overexpression alone is sufficient to induce metastasis. The ageing-ATF4 axis imposes a dependency on glutamine metabolism, revealing a therapeutically actionable vulnerability. Clinical analyses confirm that ATF4 is enriched in aged tumours and correlates with poor survival and advanced-stage disease. Collectively, these results define epigenetic ISR-ATF4 activation as a causal driver of lineage plasticity and metastasis in aged tumours, revealing a therapeutic opportunity in older patients with lung adenocarcinoma, the most common yet understudied subset of lung cancer.

PMID: 41813904 [Indexed for MEDLINE]

27. Cancer Cell. 2026 Apr 13;44(4):846-857.e3. doi: 10.1016/j.ccell.2026.02.006. Epub 2026 Mar 5.

HS-20093, a B7-H3-targeted antibody-drug conjugate in lung cancer: Results from the ARTEMIS-001 phase 1a/b trial.

This phase 1a/b study (NCT05276609) evaluated the safety, pharmacokinetics, and efficacy of B7-H3-targeted antibody-drug conjugate HS-20093 (GSK5764227) in 306 patients with previously treated advanced solid tumors. In phase 1a, 12.0 mg/kg was established as the maximum tolerated dose. Among 236 lung cancer patients who received 8.0 or 10.0 mg/kg HS-20093, the most frequent grade ≥3 treatment-related adverse events (AEs) included decreased neutrophil (25.5% vs. 50.5%) and white blood cell counts (19.7% vs. 42.4%), and anemia (16.8% vs. 34.3%), respectively. Treatment-related interstitial lung disease and AEs leading to death occurred in 3.4% and 3.8% of patients, respectively. Among response-evaluable patients, the confirmed objective response rate was 52.3% (95% CI: 39.5, 64.9) for extensive-stage SCLC (ES-SCLC, N = 65) and 22.4% (95% CI: 16.0, 29.8) for non-small cell lung cancer (NSCLC, N = 152) patients, with comparable rates between 8.0 mg/kg and 10.0 mg/kg dose cohorts across both groups. These results support further development of HS-20093, with 8.0 mg/kg

selected for phase 3 trials.

PMID: 41791381 [Indexed for MEDLINE]

28. Cancer Cell. 2026 Apr 13;44(4):858-878.e16. doi: 10.1016/j.ccell.2026.02.008. Epub 2026 Mar 5.

Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.

Small cell lung cancer (SCLC) typically displays a "cold" tumor microenvironment with a paucity of immune infiltrate. Neuroendocrine SCLC cells also profoundly repress MHC-I expression, rendering them vulnerable to NK cell-mediated cytotoxicity. Here, we confirm that neuroendocrine SCLC cells are sensitive to NK cell-mediated attack, yet the quantitative spatial profiling of the SCLC immune microenvironment in patient samples reveals that effector immune cells, including NK cells, are excluded from MHC-Ilow/neg SCLC regions. To study this biology, we develop dynamic single-cell RNA sequencing of microphysiological immune tumor environments (DynaMITE-seq) and integrate findings with spatial transcriptomics in patient tissue, unveiling the microvasculature as a major checkpoint restricting NK cell extravasation/recruitment. We demonstrate that the activation of vascular Stimulator of Interferon Genes (STING) signaling restores NK cell infiltration and killing of neuroendocrine SCLC, suggesting a strategy to overcome this key SCLC immunologic barrier and prime therapeutic response to DLL3-targeted CAR-NK cell therapy.

PMID: 41791380 [Indexed for MEDLINE]

29. J Clin Oncol. 2026 Apr;44(10):893-902. doi: 10.1200/JCO-25-01929. Epub 2026 Mar 4.

Izalontamab Brengitecan in Locally Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations Outside of Classical EGFR Mutations: A Phase Ib Study.

PURPOSE: To evaluate the safety and efficacy of izalontamab brengitecan (iza-bren) in patients with non-small cell lung cancer (NSCLC) harboring actionable genomic alterations (GAs) outside of classical epidermal growth factor receptor (EGFR) mutations.

METHODS: Eligible patients had locally advanced or metastatic NSCLC with prespecific actionable GAs, had progressed after standard treatment and received no more than one previous line of chemotherapy. iza-bren was administered at the dose of 2.5 mg/kg once per day on days 1 and 8 of each 3-week cycle. The primary end point was safety. The secondary end points included objective response rate (ORR), disease control rate (DCR), and duration of response. The exploratory end points included progression-free survival (PFS) and overall survival (OS).RESULTS: A total of 83 patients with NSCLC were enrolled in four cohorts: EGFR exon20ins/nonclassical mutations (n = 14), human epidermal growth factor receptor 2 (HER2) mutation (n = 19), KRAS/BRAF/MET mutation (n = 26), and ALK/ROS1/RET/NTRK fusion (n = 24). The most common grade ≥3 treatment-related adverse events (TRAEs) were thrombocytopenia (51.8%), anemia (44.6%), and neutropenia (43.4%). The most frequent nonhematologic TRAEs of all grades were nausea (49.4%), asthenia (45.8%), stomatitis (44.6%), and diarrhea (38.6%). One case of grade 2 interstitial lung disease was observed. The confirmed ORR was 39.7%, and the DCR was 85.9%. The median PFS was 7.0 months (95% CIs, 5.4 to 10.5), while OS data were immature. Patients with EGFR exon20ins or other nonclassical mutations achieved an ORR of 69.2% with a median PFS of 10.5 months (95% CI, 6.9 to not reached); the HER2-mutant cohort had an ORR of 52.9% and a median PFS of 7.5 months (95% CI, 5.4 to not reached).

CONCLUSION: iza-bren demonstrated encouraging antitumor activity and a manageable safety profile in pretreated NSCLC patients with diverse GAs outside of classical EGFR mutations, especially in EGFR exon20ins/nonclassical and HER2 mutations.

PMID: 41779981 [Indexed for MEDLINE]

30. JAMA Oncol. 2026 Apr 1;12(4):402-406. doi: 10.1001/jamaoncol.2025.6430.

Ancestry-Associated Performance Variability of Open-Source AI Models for EGFR Prediction in Lung Cancer.

IMPORTANCE: Artificial intelligence (AI) models are emerging as rapid, low-cost tools for predicting targetable genomic alterations directly from routine pathology slides. Although these approaches could accelerate treatment decisions in lung cancer, little is known about whether their performance is consistent across diverse patient populations and tissue contexts.

OBJECTIVE: To evaluate the performance and generalizability of 2 open-source AI pathology models for predicting EGFR mutation status in lung adenocarcinoma (LUAD) across independent cohorts and ancestral subgroups.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included patients with LUAD from 2 cohorts: Dana-Farber Cancer Institute (DFCI) from June 2013 to November 2023, and a European-based trial (TNM-I) from August 2016 to February 2022. All patients had paired next-generation sequencing data and hematoxylin-eosin-stained whole-slide images. In the DFCI cohort, genetic ancestry was inferred using germline genotype data. Data analyses were performed from July 2025 to September 2025.

MAIN OUTCOMES: The primary outcome was model performance for predicting EGFR mutation status, measured as the area under the receiver operating characteristic curve (AUC), evaluated overall and across ancestry subgroups and sample types.

RESULTS: Overall, 2098 patients with LUAD were included (mean [SD] age, 66.6 [10.3] years; 1315 female individuals [63%] and 783 male individuals [37%]). In the DFCI cohort (n = 1759; 54 African, 101 American, 95 Asian, 1465 European), EGFR mutations were detected in 432 patients (25%). One AI-pathology model achieved an AUC of 0.83 (95% CI, 0.81-0.85) compared with 0.68 (95% CI, 0.65-0.70) for the other model. In the TNM-I cohort (n = 339), EGFR mutations were detected in 50 patients (15%), with AUCs of 0.81 (95% CI, 0.74-0.88) and 0.75 (95% CI, 0.68-0.83), respectively. In ancestry-stratified analyses of the DFCI cohort, AUCs for the higher-performing model were 0.84 (95% CI, 0.81-0.86) in patients of European ancestry, 0.85 (95% CI, 0.72-0.94) in African ancestry, and 0.68 (95% CI, 0.55-0.78) in Asian ancestry. In sample type analyses, performance declined in pleural (AUC, 0.66; 95% CI, 0.56-0.76) compared with lung specimens (AUC, 0.86; 95% CI, 0.83-0.88). AI-guided triage analyses showed a potential 57% reduction in rapid EGFR testing, while maintaining sensitivity of 0.84 and specificity of 0.99.

CONCLUSIONS: This cohort study found that AI-based pathology tools may serve as preliminary adjuncts for EGFR prediction in lung cancer, though performance differences by ancestry warrant careful interpretation.

PMID: 41678173 [Indexed for MEDLINE]

31. Nat Med.2026 Apr;32(4):1233-1240. doi: 10.1038/s41591-025-04181-w. Epub 2026 Feb 2.

Time-of-day immunochemotherapy in non-small cell lung cancer: a randomized phase 3 trial.

Retrospective studies suggest that early time-of-day (ToD) infusions of immunochemotherapy may improve efficacy. However, prospective randomized controlled trials are needed to validate it. In this randomized phase 3 LungTIME-C01 trial, 210 patients with treatment naive stage IIIC-IV non-small cell lung cancer (NSCLC) lacking driver mutations were randomly assigned in a 1:1 ratio to either an early or late ToD group, defined by the administration of the first four cycles of an anti-PD-1 agent before or after 15:00 h. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS) and objective response rate (ORR). After a median follow-up of 28.7 months, the median PFS was 11.3 months (95% confidence interval (CI) = 9.2-13.4) in the early ToD group and 5.7 months (95% CI = 5.2-6.2) in the late ToD group, corresponding to a hazard ratio (HR) for earlier disease progression of 0.40 (95% CI = 0.29-0.55; P < 0.001). The median OS was 28.0 months (95% CI = not estimable (NE)-NE) in the early ToD group and 16.8 months (95% CI = 13.7-19.9) in the late ToD group, corresponding to an HR of an earlier death of 0.42 (95% CI = 0.29-0.60; P < 0.001). Treatment-related adverse events were consistent with the established safety profile, with no new safety signals observed. No significant differences in immune-related adverse events were observed between the two groups. Over the first four cycles, morning circulating CD8+ T cells increased in the early ToD group, whereas they declined in the late ToD group (P < 0.001). Furthermore, the ratio of activated (CD38+ HLA-DR+) versus exhausted (TIM-3+PD-1+) CD8+ T cells was higher in the early ToD group (P < 0.001) compared with the late ToD group (P < 0.001). In summary, our study indicates that early ToD immunochemotherapy substantially improves PFS and OS and is associated with enhanced antitumor CD8+ T cell characteristics compared with late ToD treatment. ClinicalTrials.gov registration: NCT05549037 .

PMID: 41629425 [Indexed for MEDLINE]

32. Nat Med. 2026 Apr;32(4):1337-1350. doi: 10.1038/s41591-025-04186-5. Epub 2026 Jan28

Fecal microbiota transplantation plus immunotherapy in non-small cell lung cancer and melanoma: the phase 2 FMT-LUMINate trial.

Immune checkpoint inhibitors (ICI) have improved outcomes for patients with non-small cell lung cancer (NSCLC) and melanoma, yet over half of patients exhibit primary resistance. Fecal microbiota transplantation (FMT) may overcome resistance to anti-programmed cell death protein 1 (PD-1) therapy. The clinical activity and safety of FMT plus anti-PD-1 in NSCLC or anti-PD-1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy in melanoma have not been evaluated. Here we report results from FMT-LUMINate, a multicenter, open-label, phase 2 trial assessing healthy donor FMT plus anti-PD-1 in NSCLC (n = 20) or anti-PD-1 plus anti-CTLA-4 (dual ICI) in melanoma (n = 20), in the first-line setting. Eligible patients received a single FMT via oral capsules prior to ICI initiation. The primary endpoint was objective response rate (ORR) in NSCLC. Secondary endpoints included ORR in melanoma, safety and donor-host microbiome similarity. In NSCLC, the ORR was 80% (16/20), meeting the study primary endpoint. In melanoma, the ORR was 75% (15/20). FMT was deemed safe in both cohorts by an independent data and safety monitoring committee, with no grade 3 or higher adverse events (AEs) in NSCLC and 13 (65%) patients experiencing grade 3 or higher AEs in melanoma. Shotgun metagenomic sequencing revealed that responders developed a distinct post-FMT gut microbiome composition, independent of acquired donor-recipient similarity or strain-level engraftment. Responders exhibited significantly greater loss of baseline bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, E. lavalensis and Clostridium innocuum. This finding was reproduced across three published FMT oncology trials. We recolonized antibiotic-treated, tumor-bearing mice with post-FMT stool from two responder patients, and reintroduction of the specific bacterial species that were lost after FMT abrogated the antitumor effect of ICI. Taken together, these findings confirm the clinical activity of FMT in combination with ICI and suggest that the elimination of deleterious taxa is required for FMT-mediated therapeutic benefit. ClinicalTrials.gov identifier: NCT04951583 .

PMID: 41606121 [Indexed for MEDLINE]

33. Science.2026 Apr16;392(6795):eadt1310. doi: 10.1126/science.adt1310. Epub 2026 Apr 16.

Stem cell control in the lung by an autocrine injury-activated Igf complex.

Stem cells proliferate after injury to repair damaged tissue, and chronic injury can promote cancer. However, the injury-activated signals and regulatory mechanisms, and their relationship to cancer, are poorly understood. Here, we identified insulin-like growth factor 2 (Igf2) as an injury-activated mitogen for lung neuroendocrine stem cells, which are facultative airway progenitors and a cell of origin of small-cell lung cancer in mice. Igf2 was constitutively produced by the stem cells but sequestered in the niche by coexpressed Igf binding proteins (Igfbps). Airway injury released Igf2 and induced proliferation by transiently activating Igf2 receptors and repressing retinoblastoma (Rb) tumor suppressor. Permanent pathway activation by Rb deletion initiated continuous stem cell division. Thus, beyond their classical hormonal roles in physiology, growth, and aging, Igf proteins operate locally and rapidly with Igfbp and Rb to control injury-induced stem cell proliferation and tumor initiation.

PMID: 41990161 [Indexed for MEDLINE]

34. Nat Biomed Eng. 2026 Apr;10(4):815-831. doi: 10.1038/s41551-025-01594-3. Epub 2026 Jan 21.

Lung tumouroids as a testing platform for precision CAR T cell therapy.

Lung cancer, the leading cause of cancer-related mortality, presents major challenges for both standard therapies and chimeric antigen receptor (CAR) T cell therapy due to tumour heterogeneity and resistance. Preclinical models that capture patient-specific factors are essential for personalizing treatment decisions. Here we show that matched lung tumouroids and healthy lung organoids derived from patients provide a robust platform for studying therapy responses. The tumouroids faithfully retained the molecular and histological identity of the original tumours, as confirmed by genomic, epigenomic and proteomic analyses, and accurately replicated individual patient responses to standard-of-care therapies. Importantly, the platform also revealed patient-specific CAR T cell responses, uncovering a complex interplay between target antigen density and broader, tumour-intrinsic resistance programmes. By capturing these individualized factors, our model supports rational patient selection for CAR T cell therapy in lung cancer and provides a framework for designing CAR T cells tailored to overcome resistance mechanisms in solid tumours.

PMID: 41565786 [Indexed for MEDLINE]

35. N Engl J Med. 2026 Apr 9;394(14):1409-1420. doi: 10.1056/NEJMoa2600752. Epub 2026 Mar 25.

Setidegrasib in Advanced Non-Small-Cell Lung Cancer and Pancreatic Cancer.

BACKGROUND: The KRAS p.G12D variant occurs in 5% of patients with non-small-cell lung cancer (NSCLC) and is the most common substitution variant in pancreatic ductal adenocarcinoma, occurring in 40% of patients, but no targeted therapies directed against this variant are currently approved for clinical use. Setidegrasib (ASP3082) is a first-in-class KRAS G12D-targeted protein degrader.

METHODS: We conducted this phase 1 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of setidegrasib in patients with previously treated advanced solid tumors harboring KRAS p.G12D variants. The primary objectives were to evaluate the safety profile, as indicated by dose-limiting toxic effects and adverse events (the primary end points), and to determine the phase 2 dose. Setidegrasib was administered intravenously once weekly at doses of 10 to 800 mg.

RESULTS: Overall, 203 patients were enrolled. Among the 76 patients who received setidegrasib at a dose of 600 mg, which was ultimately selected as the phase 2 dose, adverse events occurred during treatment in all the patients, with events of grade 3 or higher in 42%. Treatment-related adverse events occurred in 93% of the patients; the most common were transient infusion-related reactions (in 80%) and nausea (in 30%). Adverse events led to discontinuation in 2 patients. Among the 45 patients with NSCLC who received the 600-mg dose, 36% (95% confidence interval [CI], 22 to 51) had a partial response, the median progression-free survival was 8.3 months (95% CI, 4.1 to could not be estimated), and the estimated 12-month overall survival was 59% (95% CI, 40 to 74). Among the 21 patients with metastatic pancreatic ductal adenocarcinoma who received the 600-mg dose as second- or third-line treatment (of whom 67% received setidegrasib as third-line treatment), 24% (95% CI, 8 to 47) had a response, the median progression-free survival was 3.0 months (95% CI, 1.4 to 6.9), and the median overall survival was 10.3 months (95% CI, 4.2 to 13.0).

CONCLUSIONS: Setidegrasib was associated with antitumor activity and a low incidence of treatment discontinuation due to adverse events in patients with previously treated advanced KRAS p.G12D-mutated NSCLC or pancreatic ductal adenocarcinoma. (Funded by Astellas Pharma; ClinicalTrials.gov number, NCT05382559.).

PMID: 41879829 [Indexed for MEDLINE]