PubMed：

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

Filters applied: from 2026/02/01 - 2026/02/28.

1. Nature. 2026 Feb;650(8100):230-241. doi: 10.1038/s41586-025-09825-y. Epub 2025 Dec 10.

Uncovering the role of LINE-1 in the evolution of lung adenocarcinoma.

Understanding lung cancer evolution can identify tools for intercepting its growth1,2. Here, in a landscape analysis of 1,024 lung adenocarcinomas (LUADs) with deep whole-genome sequencing integrated with multiomic data, we identified 542 LUADs with a diverse clonal architecture. In this group, we observed divergent evolutionary trajectories based on tobacco smoking exposure, ancestry and sex. LUAD from smokers showed an abundance of tobacco-related C:G>A:T driver mutations3 in KRAS and short subclonal diversification. LUAD in people who have never smoked (hereafter, never-smokers) showed early occurrence of copy-number alterations and EGFR mutations associated with SBS5 and SBS40a mutational signatures. Tumours containing EGFR mutations exhibited long latency, particularly in female individuals of European-ancestry. Tumours from Asian never-smokers showed a short clonal evolution. Importantly, we found that the mutational signature ID24 is a marker of a previously unrecognized mechanism for LUAD evolution. Tumours with ID2 showed short latency and high long interspersed nuclear element-1 (LINE-1, hereafter L1) retrotransposon activity linked to L1 promoter demethylation. These tumours exhibited an aggressive phenotype with genomic instability, elevated hypoxia scores, low neoantigen burden, metastasis propensity and poor overall survival. Reactivated L1-retrotransposition-induced mutagenesis probably contributes to the mutational signature ID2, including through the regulation of the transcriptional factor ZNF695, a member of the KZFP family5. The complex nature of LUAD evolution creates both challenges and opportunities for screening and treatment plans.

PMID: 41372401 [Indexed for MEDLINE]

2. Nat Rev Clin Oncol. 2026 Feb 23. doi: 10.1038/s41571-026-01131-4. Online ahead of print.

Innovative approaches for lung cancer screening and interception.

Lung cancer remains the leading cause of cancer-related deaths worldwide, partly because many patients are diagnosed at late stages, highlighting the urgent need for effective early detection and intervention strategies. Low-dose computed tomography (LDCT)-based screening reduces lung cancer mortality in high-risk populations defined by age and smoking history; however, the uptake of LDCT remains low among eligible individuals. Compounding this issue, modelling studies estimate that nearly half of lung cancers occur in individuals who do not meet eligibility criteria for LDCT-based lung cancer screening under current guidelines. Moreover, LDCT-based screening has inherent limitations, including a high rate of false-positive results that can lead to unnecessary invasive procedures, as well as substantial costs that limit scalability. Major efforts have been made to identify novel biomarkers such as radiomic features and liquid biopsy assays to enhance the accuracy of lung cancer risk prediction. Furthermore, the increasing detection of pulmonary nodules by LDCT or diagnostic CT scans has highlighted the importance of therapeutic interventions that can enable interception of high-risk precancerous nodules and halt their progression to invasive disease. In this Review, we summarize the current state of lung cancer screening, the disparities and infrastructural considerations for optimal implementation, and future directions in the development of biomarkers and design of precancer interception strategies that could transform both lung cancer prevention and early intervention.

PMID: 41731061

3. Nat Med. 2026 Feb;32(2):545-552. doi: 10.1038/s41591-025-04097-5. Epub 2026 Jan 7.

Estimating the number of incorrect tuberculosis diagnoses in low- and middle-income countries.

Tuberculosis (TB) is the greatest cause of infectious disease deaths worldwide. In highly affected countries, effective TB control requires prompt identification and treatment of individuals with active disease. We examined the performance of TB case-finding in low- and middle-income countries based on a comprehensive analysis of TB diagnosis data reported to the World Health Organization. Using these data we estimated the total number of individuals correctly and incorrectly diagnosed with TB, for 111 countries with a collective 6.8 million TB notifications in 2023. Here we estimate that in 2023, 2.05 (1.83-2.27) million individuals were incorrectly diagnosed with TB (false-positives), and 1.00 (0.71-1.36) million received a false-negative diagnosis, at an assumed 25% disease prevalence among individuals evaluated for TB. As many as three of every ten TB notifications may not have TB, and many individuals with TB receive false-negative diagnoses. Compared to current diagnostic performance, scaling-up new polymerase chain reaction-based diagnostics would substantially reduce under-diagnosis but only produce a small reduction in false-positive diagnoses. Major improvements in TB diagnosis will likely require higher-sensitivity bacteriological tests combined with reduced reliance on clinical diagnosis.

PMID: 41501491 [Indexed for MEDLINE]

4. Nat Immunol. 2026 Feb 23. doi: 10.1038/s41590-026-02431-8. Online ahead of print.

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

5. Science. 2026 Feb 19:eadx9954. doi: 10.1126/science.adx9954. Online ahead of print.

Rewiring STAT signaling from the cell surface with Trikine immunotherapeutics.

Cytokines dimerize two receptor chains to activate Janus kinases and STAT transcription factors that regulate immune cells but have therapeutic liabilities. We engineered "Trikines" to compel cis formation of three-chain cytokine receptor complexes at the cell surface that induce bespoke STAT transcriptional signaling programs. Trikines co-activated pSTAT5 and pSTAT3 signatures distinct from natural cytokines, by assembling trimeric combinations of Interleukin-2 (IL-2), Interleukin-10 (IL-10), and Interleukin-21 (IL-21) receptors. In pre-clinical models, an IL-2-based-Trikine restrained terminal differentiation of T cells, promoted stemness, and enhanced durability of tumor control without observable toxicity. An IL-10-based Trikine induced immune infiltration into poorly immunogenic tumors, showing efficacy in pre-clinical models of small cell lung cancer and pancreatic cancer. Trikines obviate the need for cell engineering to customize STAT signatures and may hold potential for immunotherapy.

PMID: 41712697

6. Methods Mol Biol. 2026;3015:135-149. doi: 10.1007/978-1-0716-5154-4_11.

Chromatin Immunoprecipitation Sequencing and RNA Sequencing from Laser-Microdissected Human Lung Cancer Cells.

Genomic and epigenomic analyses are widely used in various biomedical research fields, with chromatin immunoprecipitation sequencing (ChIP-seq) representing one of the key techniques. The regulatory state of chromatin is crucial for understanding gene regulation mechanisms and the roles of transcription factors, and observing these states within native tissues using clinical specimens is particularly meaningful. One of the major advantages of ChIP-seq is its ability to comprehensively map histone modifications and transcription factor binding across the genome, especially those associated with specific functions. Additionally, it enables direct sequencing of genomic regions surrounding these modifications. Unlike techniques such as Assays for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq), which involve enzymatic digestion of nearby DNA, ChIP-seq preserves the surrounding DNA, allowing for the identification of nucleotide sequences adjacent to target proteins or histone modifications. This feature makes it especially effective for detecting single nucleotide polymorphisms (SNPs) and somatic mutations associated with allele-specific transcription factor binding or histone marks. This chapter describes a method for ChIP-seq analysis of clinical lung cancer tissue samples isolated by laser microdissection. The method is also compatible with RNA isolation and subsequent RNA-seq, enabling the acquisition of cancer cell-specific epigenomic profiles within heterogeneous tissue environments.

PMID: 41629716 [Indexed for MEDLINE]

7. Ann Intern Med. 2026 Feb;179(2):196-206. doi: 10.7326/ANNALS-25-00464. Epub 2025 Dec 16.

Eligibility and Prognostic Performance of Smoking Duration-Based Versus Pack-Year-Based U.S. National Lung Cancer Screening Criteria Across Racial and Ethnic Groups.

BACKGROUND: The U.S. Preventive Services Task Force expanded lung cancer (LC) screening eligibility in 2021 (USPSTF-2021) by decreasing the minimum number of smoking pack-years from 30 to 20. Underrepresented minorities still experience disparities in screening eligibility.

OBJECTIVE: To evaluate screening eligibility and prognostic performance of alternative smoking duration-based criteria versus USPSTF-2021 (primary outcome) and risk-based screening using the recalibrated Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial 2012 (PLCOm2012update) model (secondary outcome) across diverse racial and ethnic groups.

DESIGN: Prospective, population-based Multiethnic Cohort linked to SEER (Surveillance, Epidemiology, and End Results) registries.

SETTING: California and Hawai'i, with recruitment from 1993 to 1996.

PARTICIPANTS: 105 261 adults aged 45 to 75 years with a history of smoking.

MEASUREMENTS: Hypothetical eligibility and prognostic performance (sensitivity and specificity) in detecting 6-year LC.

RESULTS: Under USPSTF-2021, 24.0% of the cohort would be eligible for screening; a 30-year smoking duration yielded the closest eligibility rate (27.5%). Compared with USPSTF-2021, the 30-year duration criteria would reduce eligibility gaps across all races relative to Whites, most notably in African Americans (30.4% vs. 28.8% for Whites under duration-based; 21.4% vs. 30.2% for Whites under USPSTF-2021) and Latinos (25.1% vs. 28.8% for Whites under duration-based; 15.7% vs. 30.2% for Whites under USPSTF-2021). Prognostic sensitivity to identify LC within 6 years increased across all races under the 30-year duration criteria, although specificity decreased commensurately. At matched overall eligibility (27.5%), a risk-based PLCOm2012update 6-year threshold of 1.1% improved both sensitivity and specificity in the overall cohort. However, it widened the eligibility gap between Latinos and Whites (14.4% vs. 31.3%) and demonstrated lower sensitivity in Latinos than duration-based criteria (59.7% vs. 69.8%).

LIMITATIONS: Cohort geography and enrollment period may limit generalizability. Overdiagnosis was not measured.

CONCLUSION: Compared with USPSTF-2021, the 30-year duration-based criteria could reduce the eligibility gaps among African Americans and Latinos relative to Whites while improving 6-year LC detection sensitivity across all races.

PMID: 41397256 [Indexed for MEDLINE]

8. Lancet Oncol. 2026 Feb;27(2):159-168. doi: 10.1016/S1470-2045(25)00643-6. Epub 2026 Jan 12.

Aumolertinib as adjuvant therapy in resected EGFR-mutated non-small-cell lung cancer (ARTS): a double-blind, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Patients with resectable non-small-cell lung cancer (NSCLC), particularly those with EGFR mutations, face a high risk of recurrence and mortality post-surgery. Aumolertinib, a third-generation EGFR tyrosine-kinase inhibitor, is approved in China for adjuvant treatment in patients with NSCLC harbouring EGFR with an exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation. The ARTS study aimed to evaluate the efficacy and safety of adjuvant therapy with aumolertinib in patients with stage II-IIIB EGFR-mutated NSCLC.

METHODS: This double-blind, multicentre, randomised, controlled, phase 3 trial enrolled patients from 48 hospitals in mainland China. Eligible patients were 18 years or older with stage II-IIIB NSCLC, had undergone a complete resection followed by standard adjuvant therapy, and had an EGFR ex19del or Leu858Arg mutation and an Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients were stratified by EGFR mutation status and tumour stage and were randomly assigned (1:1) to receive aumolertinib 110 mg or placebo orally, once daily for 3 years or until disease recurrence or other discontinuation criteria were met. Patients were randomly allocated to groups using an interactive web response system; the double‑dummy technique masked patients, investigators, and assessors. The primary endpoint was disease-free survival in the modified intention-to treat (mITT) population (ie, all patients with stage II-IIIB NSCLC harbouring EGFR mutations who had undergone complete tumour resection and standard adjuvant therapy), assessed by blinded independent central review (BICR). Safety was assessed in all patients who received at least one dose of study treatment. Although the study is ongoing, with some patients remaining in follow-up, this analysis represents the protocol-specified primary analysis. This study is registered with ClinicalTrials.gov (NCT04687241).

FINDINGS: Between April 30, 2021, and May 17, 2022, 399 individuals were screened for study eligibility; of these, 214 patients were randomly assigned to receive aumolertinib or placebo (107 in each group). 120 (56%) patients were female, 94 (44%) were male, median age was 59 years (IQR 54-66), and all patients were Chinese. 204 (95%) of 214 patients had received prior adjuvant chemotherapy. One patient in the aumolertinib group and three patients in the placebo group had stage I disease; therefore, 106 patients in the aumolertinib group and 104 in the placebo group were included in the mITT (primary analysis) population. As of the data cutoff date (April 15, 2024), the median duration of follow-up was 27·56 months (IQR 22·18-27·70) in the aumolertinib group and 27·63 months (22·18-27·79) in the placebo group. The BICR-assessed disease-free survival was significantly improved in the aumolertinib group compared with the placebo group, with an HR of 0·17 (95% CI 0·09-0·29, p<0·0001). The median disease-free survival per BICR in the aumolertinib group was not reached (95% CI 29·14 to not applicable), whereas it was 19·42 months (11·24-26·22) in the placebo group. The most common grade 3-4 adverse events in the aumolertinib group versus the placebo group were increased blood creatine phosphokinase (seven [7%] vs none), prolonged electrocardiogram QT interval (three [3%] vs three [3%]), hypertension (one [1%] vs five [5%]), and pneumonia (two [2%] vs three [3%]). Treatment-related serious adverse events occurred in one (1%) patient receiving aumolertinib and three (3%) patients receiving placebo. No treatment-related deaths occurred and no new safety signals were identified for aumolertinib.

INTERPRETATION: Aumolertinib showed substantial clinical benefits as adjuvant therapy in Chinese patients with stage II-IIIB EGFR-mutated NSCLC. The manageable safety profile of aumolertinib supports its suitability in the adjuvant setting.

PMID: 41539318 [Indexed for MEDLINE]

9. JAMA Oncol. 2026 Feb 1;12(2):167-176. doi: 10.1001/jamaoncol.2025.5672.

Enhancement of Patient-Centered Lung Cancer Screening: The My Lung Health Randomized Clinical Trial.

IMPORTANCE: Lung cancer screening (LCS) with low-dose computed tomography (CT) remains underused in the US, partly because of incomplete smoking history documentation in electronic health records (EHRs) and limited time for shared decision-making in primary care.

OBJECTIVE: To determine whether a patient-facing, EHR-integrated tool combined with clinician-facing clinical decision support improves the identification of LCS-eligible patients and the ordering of low-dose CT compared with clinician-facing tools alone.

DESIGN, SETTING, AND PARTICIPANTS: This pragmatic, unstratified, randomized clinical trial with parallel groups was conducted from March 29, 2024, to March 28, 2025, at primary care clinics at University of Utah Health and New York University Langone Health. Adults aged 50 to 79 years with a documented smoking history, an active patient portal account, and a primary care visit in the preceding year were included. Study 1 enrolled patients with uncertain LCS eligibility (10 to 19 pack-years, unknown pack-years, or missing quit date); study 2 enrolled patients with documented eligibility (20 or more pack-years and currently smoking or quit smoking within 15 years).

INTERVENTIONS: The control included the clinician-facing Decision Precision+ tool (preventive care reminders and a shared decision-making tool). The intervention included the Decision Precision+ tool as well as the My Lung Health tool, which collected detailed smoking history (study 1) and delivered personalized education and risk/benefit information (studies 1 and 2) via the patient portal in English and Spanish.

MAIN OUTCOMES AND MEASURES: The primary outcomes were the proportion of patients newly identified as eligible for LCS (study 1) and low-dose CT ordering rates (study 2) over 12 months. Analyses used intention-to-treat mixed-effects logistic regression.

RESULTS: There were 31 303 randomized participants, including 26 729 in study 1 (13 144 [49.2%] female; 13 580 [50.8%] male; median [IQR] age, 62 [55-69] years) and 4574 in study 2 (2230 [48.8%] female; 2344 [51.2%] male; median [IQR] age, 63 [56-69] years). In study 1, the My Lung Health tool increased new LCS eligibility identification (635 of 13 412 [4.7%] vs 308 of 13 317 [2.3%]; adjusted odds ratio, 2.19; 95% CI, 1.99-2.42; P < .001). In study 2, low-dose CT ordering was higher in the intervention arm (474 of 2312 [20.5%] vs 434 of 2262 [19.2%]; adjusted odds ratio, 1.16; 95% CI, 1.04-1.30; P = .008).

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, integrating a patient-centered tool into primary care EHR workflows increased the identification of patients eligible for LCS and the ordering of low-dose CTs. The relative increases in these primary outcomes were substantial, but absolute increases were more modest. Research on more intensive interventions is warranted to evaluate their ability to further improve LCS screening.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06338592.

PMID: 41452617 [Indexed for MEDLINE]

10. Lancet Respir Med. 2026 Feb;14(2):117-128. doi: 10.1016/S2213-2600(25)00263-2. Epub 2025 Dec 4.

First-line serplulimab plus chemotherapy with or without HLX04 versus chemotherapy in locally advanced or metastatic non-squamous non-small-cell lung cancer (ASTRUM-002): a randomised, double-blind, multicentre phase 3 trial.

BACKGROUND: Whether the addition of bevacizumab to a programmed cell death protein-1 (PD-1) inhibitor plus chemotherapy can provide further survival benefits as first-line treatment in non-squamous non-small-cell lung cancer (NSCLC) without EGFR sensitising mutations, or ALK/ROS1 rearrangements, is unknown. We evaluated serplulimab (an anti-PD-1 antibody) plus HLX04 (a bevacizumab biosimilar) and chemotherapy in non-squamous NSCLC.

METHODS: ASTRUM-002 is a randomised, double-blind, multicentre, phase 3 trial with a three-arm design. Patients (aged ≥18 years and ≤75 years) with locally advanced or metastatic non-squamous NSCLC without EGFR sensitising mutations or ALK/ROS1 rearrangements and previous systemic therapy were randomly assigned (1:1:1; stratified by PD-L1 expression, smoking history, and brain metastasis) to receive serplulimab (4·5 mg/kg intravenously) plus HLX04 (15 mg/kg intravenously) and chemotherapy (pemetrexed and carboplatin; group A), serplulimab plus chemotherapy plus HLX04 placebo (group B), or chemotherapy plus serplulimab placebo plus HLX04 placebo (group C). The primary endpoint was the blinded independent central review assessed progression-free survival per the Response Evaluation Criteria in Solid Tumors version 1.1, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03952403, and is complete.

FINDINGS: Between Nov 25, 2019, and June 15, 2022, 642 patients were enrolled across 72 hospitals in China; six in the safety run-in phase and the remaining 636 patients were randomised to group A (212 patients), B (214), or C (210). 465 (73%) were male, 171 (27%) were female, and 599 (94%) were of Han ethnicity. By the data cutoff date of June 15, 2023, the median follow-up duration was 23·4 months (95% CI 21·6-24·9) in group A, 23·1 (21·4-25·6) in group B, and 23·0 (20·7-25·6) in group C. Median progression-free survival was 12·6 months (95% CI 8·7-14·0; 123 events) in group A, 11·0 months (95% CI 8·4-12·7; 130 events) in group B, and 5·6 months (95% CI 4·8-6·8; 156 events) in group C. A significant reduction was seen in risk of progressive disease or death for patients in group B compared with group C (hazard ratio [HR] 0·55, 95% CI 0·43-0·69; p<0·0001). No significant improvement in progression-free survival was seen for group A compared with group B (HR 0·86, 0·67-1·11; p=0·25). Treatment-related serious adverse events occurred in 82 (39%) patients in group A, 79 (37%) in group B, and 51 (24%) in group C. Grade 3 or worse treatment-related adverse events occurred in 149 (71%) patients in group A, 142 (66%) in group B, and 119 (57%) in group C. Treatment-related adverse events leading to death occurred in ten (5%) patients in group A, five (2%) in group B, and seven (3%) in group C.

INTERPRETATION: The addition of serplulimab to chemotherapy led to significantly longer progression-free survival in patients with locally advanced or metastatic non-squamous NSCLC compared with chemotherapy alone and represents an alternative first-line treatment option for this patient population. HLX04 plus serplulimab and chemotherapy did not confer further statistical benefit compared with serplulimab plus chemotherapy.

PMID: 41354044 [Indexed for MEDLINE]

11. Lancet Respir Med. 2026 Feb;14(2):163-173. doi: 10.1016/S2213-2600(25)00258-9. Epub 2025 Nov 29.

Glecirasib plus sitneprotafib in patients with KRAS(G12C)-mutated non-small-cell lung cancer in China: an open-label, multicentre, single-arm, phase 1/2a trial.

BACKGROUND: Monotherapy with KRASG12C (ie, KRAS Gly12Cys) inhibitors has emerged as a mainstream treatment for patients with KRASG12C -mutated non-small-cell lung cancer (NSCLC). Synergistic effects have been observed with the combination of a KRASG12C inhibitor and a SHP2 inhibitor in multiple xenograft models. We aimed to evaluate the safety and efficacy of the KRASG12C inhibitor glecirasib combined with the SHP2 inhibitor sitneprotafib (JAB-3312; Jacobio Pharmaceuticals, Beijing, China) in patients with KRASG12C -mutated solid tumours.

METHODS: We conducted an open-label, multicentre, single-arm, phase 1/2a trial at 26 hospitals across China. Patients (aged ≥18 years) with locally advanced or metastatic solid tumours harbouring a KRASG12C mutation, an Eastern Cooperative Oncology Group performance status score of 0-1, and measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST; version 1.1) were eligible for inclusion in both phases. Patients received oral glecirasib (400 mg or 800 mg once daily) in combination with oral sitneprotafib (2 mg or 3 mg once daily) in seven cohorts evaluating various dose levels and schedules of the two drugs. In phase 1, the primary endpoint was safety assessed by investigators according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) from first treatment dose to 30 days after the last dose of both agents. In phase 2a, the primary endpoint was objective response rate (ORR) between baseline and disease progression or initiation of anticancer therapy, whichever occurred first, based on the comprehensive assessment of all tumour evaluations by investigators following RECIST (version 1.1). All patients who received at least one dose of combination therapy were included in the safety and efficacy analyses. This trial is registered with ClinicalTrials.gov (NCT05288205) and is currently recruiting.

FINDINGS: Between May 7, 2022, and Aug 20, 2024, a total of 194 patients with advanced solid tumours were enrolled, of whom 171 (88%) had NSCLC (50 [29%] in phase 1 and 121 [71%] in phase 2a). Median participant age was 65 years (IQR 59-70); 140 (82%) were men and 31 (18%) were women. At data cutoff on Aug 20, 2024, the median follow-up duration was 14·5 months (IQR 11·9-17·1), and 106 (62%) patients had discontinued treatment. Phase 1 concluded with one dose-limiting toxicity (DLT; grade 3 pneumonitis) at the highest dose level (glecirasib 800 mg plus sitneprotafib 3 mg once daily, 1 week on and 1 week off); no DLTs were observed at other dose levels. Across phase 1 and 2a, 167 patients (98%) had at least one treatment-related adverse event, which were grade 3-4 in 78 (46%) patients. The most common treatment-related adverse events (occurring in ≥20% of all 171 patients) were anaemia (105 [61%]), hypertriglyceridaemia (103 [60%]), increased aspartate aminotransferase (95 [56%]), increased alanine aminotransferase (83 [49%]), increased blood bilirubin (78 [46%]), oedema (62 [36%]), increased blood creatine phosphokinase (60 [35%]), neutropenia (54 [32%]), decreased white blood cell count (50 [29%]), and increased bodyweight (44 [26%]). Three (2%) patients discontinued glecirasib and sitneprotafib due to treatment-related adverse events. No grade 5 treatment-related adverse event was reported. The ORR was 71% (72 patients [95% CI 61-79]) in the subgroup of 102 patients with previously untreated NSCLC; 49% (19 patients [32-65]) in the 39 patients previously treated with systemic therapy but naive to KRASG12C inhibitors; and 10% (three patients [2-27]) in the 30 patients previously treated with KRASG12C inhibitor therapy.

INTERPRETATION: Glecirasib combined with sitneprotafib showed promising efficacy and manageable safety in patients with advanced KRASG12C -mutated NSCLC, particularly among those who had not received previous treatment. These findings support the evaluation of this combination in a phase 3 trial comparing this chemotherapy-free regimen to current standard of care in this patient group.

PMID: 41325755 [Indexed for MEDLINE]

12. Nat Cell Biol. 2026 Feb;28(2):338-348. doi: 10.1038/s41556-025-01840-5. Epub 2026 Jan 7.

SLC2A1(+) tumour-associated macrophages spatially control CD8(+) T cell function and drive resistance to immunotherapy in non-small-cell lung cancer.

Tumour-associated macrophages (TAMs) contribute to immune checkpoint blockade resistance, but their impact on intratumoural CD8⁺ T cell distribution remains unclear. Here we show that the expression of the glucose transporter SLC2A1 is spatially negatively correlated with CD8⁺ T cell distribution in both non-small-cell lung cancer (NSCLC) biopsies and murine tumour models. Tumour cell-specific Slc2a1 knockdown fails to reproduce the therapeutic benefit of SLC2A1 inhibition, whereas TAM-specific deletion of Slc2a1 suppresses tumour growth by enhancing the spatial homogeneity and effector function of intratumoural CD8⁺ T cells, thereby improving αPD-L1 efficacy. Spatial profiling of NSCLC specimens further revealed that SLC2A1⁺ TAM-enriched regions exhibit reduced CD8⁺ T cell density, and spatial proximity between these populations predicts resistance to αPD-(L)1 therapy. These findings identify SLC2A1⁺ TAMs as drivers of spatial CD8⁺ T cell exclusion and highlight TAM-specific SLC2A1 as a therapeutic target to overcome immune checkpoint blockade resistance in NSCLC.

PMID: 41501177 [Indexed for MEDLINE]

13. Nat Rev Clin Oncol. 2026 Mar;23(3):201-212. doi: 10.1038/s41571-025-01112-z. Epub 2026 Jan 7.

A guide to cancer screening.

The aim of cancer screening is to identify pre-malignant conditions, which can be removed or treated, or earlier-stage disease, for which treatment is more likely to be curative, in non-symptomatic individuals. Currently, screening programmes are being consolidated for five cancer types (breast, prostate, cervical, colorectal and lung) and several other cancer types are the focus of specific initiatives. Cancer screening is at a point of potential major transformation owing to technological advances in detection. In this Review, we first recapitulate the general principles of cancer screening. We then provide a timely overview of the current screening practices for breast, cervical, colorectal, prostate and lung cancer, addressing major challenges and potential future changes in practice. We also discuss other malignancies for which screening initiatives might be worth considering. Finally, we highlight technological developments in cancer detection that might hold promise for screening an increasing number of cancers in the future, notably some that reflect unmet needs.

PMID: 41501152 [Indexed for MEDLINE]

14. Lancet Glob Health. 2026 Mar;14(3):e356-e366. doi: 10.1016/S2214-109X(25)00494-2.

Avoidable deaths through the primary prevention, early detection, and curative treatment of cancer worldwide: a population-based study.

BACKGROUND: Global disparities exist in cancer incidence, mortality, and survival. We aimed to provide estimates of avoidable deaths among people diagnosed with cancer to inform the prioritisation of interventions and narrow cancer inequalities.

METHODS: National incidence estimates for 35 cancer sites in 2022 for 185 countries were extracted from the GLOBOCAN database. We estimated numbers of avoidable deaths within 5 years of diagnosis for patients diagnosed with cancer in 2022, consisting of those deaths avoidable through primary prevention (preventable deaths) and those avoidable through early detection and improved access to treatment (treatable deaths) by cancer site, country, region, and human development index (HDI) group. Preventable deaths were estimated using population attributable fractions for tobacco use, alcohol consumption, excess body weight, infectious agents, and ultraviolet radiation obtained from the literature. Treatable deaths were estimated by eliminating survival differences using 5-year net survival from the SURVCAN-3 project and additional sources. Preventable, treatable, and overall avoidable deaths as proportions of the total expected deaths within 5 years of cancer diagnosis were also calculated.

FINDINGS: 5 years after cancer diagnosis, 4·5 million (47·6% [95% uncertainty interval 47·5-47·8]) of the 9·4 million expected deaths were avoidable. Of these avoidable deaths, 3·1 million (3·1-3·1; 33·2% [33·1-33·3] of total expected deaths) were preventable and 1·4 million (1·4-1·4; 14·4% [14·4-14·5]) were treatable. Lung, liver, stomach, colorectal, and cervical cancers contributed the greatest burden, collectively accounting for 59·1% of all avoidable deaths. Lung cancer was responsible for the most preventable deaths (1·1 million; 34·6% of all preventable deaths), while female breast cancer was responsible for the most treatable deaths (0·2 million; 14·8% of all treatable deaths). Disproportionately large proportions of avoidable deaths from cervical and breast cancer were observed in countries with a low or medium HDI.

INTERPRETATION: Nearly half of deaths among people diagnosed with cancer globally could be avoided through primary prevention and improvements in early detection and curative cancer treatment. Global efforts are needed to tailor prevention, early diagnosis, and treatment of cancer to address inequities in avoidable deaths, especially in low and medium HDI countries.

FUNDING: Erasmus Mundus Exchange Programme and French National Cancer Institute (INCa).

PMID: 41713439 [Indexed for MEDLINE]

15. Cell. 2026 Feb 5;189(3):906-921.e20. doi: 10.1016/j.cell.2025.12.009. Epub 2026 Jan 7.

EcDNA-borne structural variants drive oncogenic fusion transcript amplification.

Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole-genome and transcriptome sequences from tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy-number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1-with exon 1 joined to diverse 3' partners-confers increased RNA stability, potentially via an SRSF1-dependent mechanism, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation in cancer.

PMID: 41506267 [Indexed for MEDLINE]

16. Adv Mater. 2026 Feb;38(9):e16974. doi: 10.1002/adma.202516974. Epub 2025 Dec 12.

Effective Degradation of Wild-Type and Mutant EGFR Using Self-Assembling Peptide-Derived PROTAC Nanoparticles (NanoTACs) for Cancer Therapy.

Epidermal growth factor receptor (EGFR)-targeted therapeutics, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have achieved clinical success but are limited by drug resistance and off-target toxicity. Herein, self-assembling peptide-derived PROTAC nanoparticles (NanoTACs) engineered for effective degradation of both wild-type and mutant EGFR for cancer therapy is reported. The NanoTACs are constructed from three peptide components: EGFR-binding peptide (EHGAMEI), a self-assembling peptide linker (FF), and an E3 ligase recruiting peptide (ALAPYIP). Through the hydrophobic interaction and π-π stacking, self-assembling peptide-derived PROTACs formed uniform spherical nanoparticles with an average diameter of 144 nm under aqueous conditions. In vitro, NanoTACs effectively eliminated both wild-type and L858R/T790M-mutant EGFR in cancer cells through direct lysosomal degradation and PROTAC-driven proteasomal degradation. In vivo, NanoTACs exhibited 2.24-fold higher tumor-targeting efficiency than free EGFR-binding peptide via the enhanced permeability and retention (EPR) effect and EGFR-mediated active targeting. In colon and lung tumor models, NanoTACs suppressed tumor growth by 88.3%, achieved 95% degradation of wild-type and 80% of mutant EGFR, and induced extensive apoptosis without systemic toxicity. These findings established NanoTACs as a promising EGFR-targeted platform to overcome drug resistance to mAbs and TKIs by enabling effective degradation of wild-type and mutant EGFR in heterogeneous cancers.

PMID: 41386736 [Indexed for MEDLINE]

17. Nat Rev Clin Oncol. 2026 Feb 18. doi: 10.1038/s41571-026-01123-4. Online ahead

of print.

Reconsidering adjuvant and perioperative immune-checkpoint inhibition: de-escalation, expansion and personalization.

Anti-PD-L1 antibodies have transformed cancer treatment and are increasingly being used in patients with early-stage malignancies including in the adjuvant and neoadjuvant settings. In certain cancers, earlier administration of these agents reduces the risk of metastatic disease and might improve overall survival. Thus far, however, overall survival benefits in the adjuvant setting have yet to be clearly demonstrated in all tumour types probably owing to a lack of long-term follow-up and/or the confounding effects of anti-PD-L1 antibody monotherapy and/or combinations in the metastatic setting, in which these agents can also produce durable responses. In this Review, we explore the optimal use of anti-PD-L1 antibodies in the adjuvant and perioperative settings, using examples from melanoma, renal cell carcinoma and non-small-cell lung cancer. We examine de-escalation strategies, including shortening treatment duration or deferring therapy to time of recurrence, at which point anti-PD-L1 antibodies might be more likely to be administered in combination; the expansion of certain specific indications, potentially leading to more effective combinations and/or use in biomarker-defined patients with high-risk early-stage disease; and selecting the most appropriate indication, with emerging data suggesting that neoadjuvant or perioperative use of anti-PD-L1 antibodies might be more effective than adjuvant use in certain cancers, as well as the possibility of personalization of therapy guided by biomarkers such as circulating tumour DNA or other emerging assays.

PMID: 41708831

18 Circulation 2026 Feb 17;153(7):516-533. doi:10.1161/CIRCULATIONAHA. 125.079067. Epub 2026 Jan 28.

Breast Cancer Reveals Latent BMPR2-Related Susceptibility to Pulmonary Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) and breast cancer disproportionately affect women. BMPR2 (bone morphogenetic protein receptor type 2) mutations, the most common genetic cause of heritable PAH, also exert tumor-suppressive functions, but their role in linking these diseases remains unclear.

METHODS: We combined bioinformatic, epidemiologic, and experimental approaches. Public cancer datasets were mined for BMPR2 alterations. In vivo, mammary tumor development and pulmonary hemodynamics were assessed in female Bmpr2+/Δ71 rats with or without carcinogen (7,12-dimethylbenz[a]anthracene) exposure. Pulmonary arterial smooth muscle cells were exposed to tumor-conditioned media to test inflammatory proliferation. Finally, associations between breast cancer and PAH were examined in the French National Healthcare Database (9964 patients with PAH).

RESULTS: BMPR2 expression was markedly reduced in human breast tumors, with recurrent somatic variants and deep deletions identified. Bmpr2+/Δ71 rats exhibited spontaneous mammary tumors and, following 7,12-dimethylbenz[a]anthracene exposure, developed exacerbated pulmonary hypertension with increased vascular remodeling and inflammation. Tumor-bearing Bmpr2+/Δ71 rats showed elevated lung IL-1β and NF-κB activation. In vitro, conditioned media from Bmpr2+/Δ71 tumors induced proliferation of Bmpr2+/Δ71 pulmonary arterial smooth muscle cells via IL-1β-dependent signaling, while neutralization of IL-1β attenuated this effect. Human pulmonary arterial smooth muscle cells carrying BMPR2 mutations similarly displayed heightened IL-1β-induced proliferation. Epidemiologically, breast cancer incidence was more than doubled in patients with PAH compared with the general population, and PAH incidence was increased nearly 9-fold among patients with breast cancer, indicating a bidirectional relationship.

CONCLUSIONS: These findings identify a reciprocal association between breast cancer and PAH mediated by defective BMPR2 signaling and tumor-associated inflammation. Breast cancer may act as a "second hit," unmasking BMPR2-related susceptibility to PAH, underscoring BMPR2 as a shared molecular vulnerability with implications for surveillance of at-risk populations.

PMID: 41603037 [Indexed for MEDLINE]

19. Nat Med. 2026 Feb;32(2):690-701. doi: 10.1038/s41591-025-04086-8. Epub 2026 Jan 6.

Real-world clinical utility of comprehensive genomic profiling in advanced solid tumors.

Comprehensive genomic profiling (CGP) is crucial in precision oncology, yet its real-world utility remains unclear. Here we analyzed data from the Japanese nationwide Center for Cancer Genomics and Advanced Therapeutics database, including clinical and genetic data from 54,185 patients with advanced solid tumors (consisting of 81 common and rare tumor types) who received CGP with a targeted sequencing panel covering 324 genes as part of their clinical care. We assessed the prognostic value of CGP-guided clinical evidence-level classification, showing that alterations predicting response to Pharmaceuticals and Medical Devices Agency-approved or Food and Drug Administration-approved therapies and to therapies supported by well-powered studies with expert consensus are detected in 16.6% and 8.1% of patients, respectively, and are associated with better prognosis than those with lower clinical evidence levels. Only 8% of patients receive CGP-guided approved-experimental genomic biomarker-linked therapies, although the proportion has improved over time. Substantial differences were observed across tumor types, with the proportions exceeding 20% in thyroid and lung cancers but remaining below 2% in pancreatic and liver cancers. Tumor-agnostic biomarker analyses reveal that tumor mutational burden (TMB) ≥20 mutations per megabase predicts better outcome across tumor types, regardless of microsatellite instability status, in TMB-high patients receiving pembrolizumab. Conversely, extramammary Paget's disease is exceptionally resistant to pembrolizumab. The large-scale nationwide database allows evaluating inter-tumor type differences and investigating evidence-scarce situations, delineating where CGP offers greater benefit. These real-world findings complement those from clinical trials and prospective sequencing projects regarding CGP, providing valuable information for individualized treatment.

PMID: 41495408 [Indexed for MEDLINE]

20. JAMA Oncol. 2026 Feb 1;12(2):185-193. doi: 10.1001/jamaoncol.2025.5549.

Baseline Fatigue and Severe Toxic Effects in Patients With Cancer Receiving Systemic Therapy.

IMPORTANCE: Fatigue is a common symptom reported by patients with cancer, yet its role as a predictor of treatment-related toxic effects has not been well characterized. Understanding whether fatigue measured at treatment initiation may be associated with subsequent toxic effects could help guide individualized treatment planning and symptom monitoring.

OBJECTIVE: To evaluate the association between baseline patient-reported fatigue and the risk of adverse events (AEs) in cancer treatment trials.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study and pooled analysis assessed baseline fatigue data from 17 SWOG phase 2 and 3 trials conducted from 1990 to 2022. Patients were enrolled across multiple cancer types and treatment settings. Data analysis was performed from March 1, 2023, to October 17, 2025.

EXPOSURES: Baseline fatigue, classified on a 5-point Likert scale, analyzed as binary thresholds (eg,<some vs ≥some fatigue) and across fatigue severity levels.

MAIN OUTCOMES AND MEASURES: Adverse events were classified using the Common Terminology Criteria for Adverse Events (CTCAE), with multiple versions mapped to version 4. Symptomatic AEs followed the Patient-Reported Outcomes-CTCAE framework; laboratory-based or measurable toxic effects were considered objective (hematologic vs nonhematologic). Primary outcomes were grade 3 or higher (severe), grade 4 or higher (life-threatening), and grade 5 (fatal) AEs. Odds ratios (ORs) were estimated using generalized estimating equations. To account for confounding, the analysis was clustered by trial and adjusted for age, sex, race, and obesity.

RESULTS: Among 7086 patients (mean [SD] age, 62.1 [15.2] years; 2107 females [29.7%] and 4979 males [70.3%]) with prostate, lung, colorectal, lymphoma, breast, melanoma, ovarian, or pancreatic cancer, 103 738 AEs were reported. At baseline, 2771 participants (39.1%) reported some or more fatigue. Proportions with maximum AEs rated grade 3 or higher, grade 4 or higher, and grade 5 were 3128 participants (44.1%), 1001 (14.1%), and 62 (0.9%), respectively. Compared with those reporting no or minimal fatigue, patients with some fatigue or more had higher risks of severe or worse toxic effects (odds ratio [OR], 2.09; 95% CI, 1.58-2.78; P < .001), life-threatening or fatal toxic effects (OR, 1.96; 95% CI, 1.36-2.82; P < .001), and fatal toxic effects (OR, 2.35; 95% CI, 1.07-5.19; P = .03). A dose-response pattern was evident: patients reporting quite a lot or very much fatigue had an approximately 5-fold higher risk of fatal toxic effects (OR, 4.99; 95% CI, 1.84-13.51; P = .002). Findings were consistent across symptomatic, hematologic, and nonhematologic AE categories.

CONCLUSIONS AND RELEVANCE: This cohort study found that baseline patient-reported fatigue was associated with an increased risk of cancer treatment-related toxic effects. Fatigue assessments at treatment initiation may serve as an early clinical marker of risk for toxic effects and may help inform personalized treatment strategies and symptom monitoring.

PMID: 41452615 [Indexed for MEDLINE]

21. Nat Mater. 2026 Feb;25(2):310-321. doi: 10.1038/s41563-025-02391-8. Epub 2025 Oct 31.

Tumour priming by ultrasound mechanogenetics for CAR T therapy.

Cell-based cancer immunotherapy holds potential as a therapeutic approach, yet its application for solid tumour treatment remains challenging. Here we report a focused-ultrasound-based approach that mechanically induces the localized expression of CD19 antigen within a subpopulation of cells within solid tumours, which function as local 'training centres' to activate chimeric antigen receptor T cells. Activated chimeric antigen receptor T cells attack the whole cancer cell population near the tumour site, thus achieving cancer suppression. The system achieves targeted gene expression by integrating focused-ultrasound-triggered mechanical stimulation and the subsequent calcium response of cancer cells with a doxycycline-gated AND-logic genetic circuit, both of which need to be active for effective induction of CD19 expression. We validate the functionality of the approach in vitro, in organoids and in vivo, achieving direct control of user-designed gene expressions through FUS-mediated mechanical stimulation without the need of any cofactor, demonstrating the approach's potential as a versatile platform for precisely controllable immunotherapy. Overall, our combinatorial approach offers a focused-ultrasound-controlled remote and non-invasive priming of solid tumours for effective and safe chimeric antigen receptor T cell immunotherapy via the induced production of clinically validated antigens.

PMID: 41174038 [Indexed for MEDLINE]

22. Lancet Glob Health. 2026 Mar;14(3):e444-e454. doi: 10.1016/S2214-109X(25) 00478-4.

The tuberculogenic environment.

Tuberculosis persists as the world's deadliest infectious disease, despite improved diagnostics and effective treatment. The tuberculogenic environment describes the sum of influences, vulnerabilities, policies, life conditions, and health factors that sustain the tuberculosis pandemic in vulnerable communities. The persistence of these environments is attributable to challenges upstream of the health system, involving sectors such as trade, taxation, finance, agriculture, employment, social services, and education. The availability, affordability, access, and acceptability of safe infrastructure (including housing), nutritious foods, protection against harmful consumption (tobacco, alcohol, sugar, etc), and adequately resourced health services are all linked to tuberculosis risk. Yet people affected by tuberculosis and national tuberculosis control programmes continue to bear almost the sole responsibility for a problem that is largely beyond their control. Reframing tuberculosis through the lens of complex systems science highlights the array of decision makers who, by action or inaction, have a shared responsibility to end tuberculosis as a global pandemic.

PMID: 41713446 [Indexed for MEDLINE]

23. Lancet Glob Health. 2026 Mar;14(3):e347-e355. doi: 10.1016/S2214-109X(25) 00454-1.

Characterising progression and regression patterns across the spectrum of tuberculosis: a multistate modelling approach.

BACKGROUND: The conceptualisation of tuberculosis has undergone a paradigm shift from binary states to a spectrum, resulting in the International Consensus for Early TB (ICE-TB) framework. This study aimed to use data from a prospective, observational cohort study and multistate modelling to address the lack of contemporary data to quantify movement between ICE-TB states.

METHODS: ERASE-TB was a prospective, observational cohort study evaluating novel diagnostic tests for earlier detection of tuberculosis. Household contacts aged at least 10 years in Zimbabwe, Tanzania, and Mozambique were followed up 6-monthly for 12-24 months with comprehensive tuberculosis investigations at each visit. Those not diagnosed with prevalent tuberculosis, with state classification from at least two timepoints were included. ICE-TB states were defined by use of symptomatology, interferon gamma release assays, chest radiographs, and sputum microbiology. A Markov multistate model based on ICE-TB was applied with one initial state (Mycobacterium tuberculosis non-infection), two intermediate states (M tuberculosis infection and non-infectious disease [asymptomatic-symptomatic]), and one absorbing state (infectious disease [asymptomatic-symptomatic]). Transition probabilities were predicted.

FINDINGS: 1789 (84·8%) of 2109 recruited household contacts were included. At enrolment, most (1000 [55·9%]) did not have M tuberculosis infection; 674 (37·7%) had M tuberculosis infection, and 115 (6·5%) had non-infectious disease. 34 people developed infectious disease (23 asymptomatic, 11 symptomatic). In the multistate model, the transition probabilities of progressing from M tuberculosis non-infection to M tuberculosis infection and M tuberculosis infection to non-infectious disease were 13% and 3% by month 12. For those in non-infectious disease, the probabilities of regression and progression by month 12 were 85% and 13%, respectively.

INTERPRETATION: This study applied the ICE-TB framework to describe movement between states by use of contemporary, granular, longitudinal data. Although most people remained static over time, the non-infectious state was more dynamic, with most people regressing over time.

PMID: 41713438 [Indexed for MEDLINE]

24. Cancer Discov. 2026 Feb 6;16(2):345-366. doi: 10.1158/2159-8290.CD-24-1224.

Glucocorticoids Unleash Immune-dependent Melanoma Control through Inhibition of the GARP/TGFβ Axis.

Half of patients with advanced melanoma fail to benefit from immune checkpoint blockade, and novel treatments are urgently required. Testing topical medications for anticancer activity in an immunotherapy-resistant murine melanoma model, we found that, counterintuitively, glucocorticoids (GCs) elicit rapid cytotoxic T lymphocyte (CTL)-dependent tumor control. Genetic ablation of the GC receptor in different cellular compartments revealed that GCs acted not on immune cells but directly on tumor cells to downregulate the expression of glycoprotein A repetitions predominant (GARP). This inhibited TGFβ signaling and unleashed CTL killing. In agreement, GCs stimulated tumor control in multiple cancer models but only if the tumors also responded to pharmacologic inhibition of TGFβ signaling. Furthermore, patients with melanoma with high GC receptor expression or signaling showed improved prognosis and lower TGFβ signaling in tumor-infiltrating CTLs. Additionally, elevated GARP expression correlated with reduced survival, including in immunotherapy-treated patients. Thus, the GARP/TGFβ axis emerges as a GC-sensitive cancer cell-intrinsic immune-evasive mechanism.

SIGNIFICANCE: This study uncovers a surprising role for GCs in triggering CD8+ T cell-dependent tumor control through downregulation of GARP and thus TGFβ signaling. Analysis of samples from patients with melanoma suggested that GARP expression may serve as both a biomarker of poor antitumor immunity and a therapeutic target to improve the response to immunotherapy. See related commentary by Roest et al., p. 198.

PMID: 41086837 [Indexed for MEDLINE]

25. Lancet Glob Health. 2026 Mar;14(3):e337-e346. doi: 10.1016/S2214-109X(25) 00431-0. Epub 2026 Jan 7.

Global estimates of tuberculosis incidence during pregnancy and postpartum: a rapid review and modelling analysis.

BACKGROUND: Despite known maternal, perinatal, and infant health risks of tuberculosis during pregnancy, global estimates of incidence remain scarce. Existing estimates are outdated, and do not include the postpartum period, HIV co-infection, age, or specific changes in risk, limiting our understanding of the true scale of disease in this understudied population.

METHODS: In this rapid review and modelling analysis, we estimated the global tuberculosis incidence in pregnant and postpartum women using a population-based modelling approach. We searched MEDLINE and EMBASE, with no date or language limits, and included studies reporting tuberculosis incidence in pregnancy or postpartum with suitable comparison groups; we also used Feb 6, 2025, interim data from the ongoing ORCHID cohort. We combined WHO age and sex-stratified tuberculosis incidence data with country-specific population and fertility data to estimate baseline tuberculosis incidence, and applied systematic review-based risk ratios to account for elevated increased risk during pregnancy and postpartum. Uncertainty in all inputs was propagated using standard error propagation formulae and summarised as mean tuberculosis incidence rates and mean incidence rate ratios (IRRs), each reported with 95% quantile-based uncertainty intervals (UIs).

FINDINGS: We identified 37 studies published between 1996 and 2020, of which three were of sufficient quality to provide data for HIV-negative women. One additional study (ORCHID; Odayar et al, unpublished) provided data for women living with HIV. Compared with non-pregnant women without HIV, tuberculosis IRRs were 1·34 (95% CI 1·17-1·54) during pregnancy and 1·91 (1·53-2·39) during postpartum among HIV-negative women. For women living with HIV, IRRs were 5·73 (95% CI 2·64-10·94) during pregnancy and 3·58 (0·85-9·63) postpartum. We estimated 239 500 pregnant women (95% UI 216 300-262 800) and 97 600 postpartum women (90 100-105 200) developed tuberculosis disease globally in 2023, with HIV contributing to 21·3% (19·8-22·8) and 10·6% (9·9-11·3) of cases, respectively. The WHO African region had the highest incidence (110 600 [95% UI 96 700-124 500] in pregnant women and 40 900 [36 300-45 400] in postpartum women), followed by the South-East Asia region (79 900 [64 100-95 700] in pregnant women and 35 900 [30 800-41 100] in postpartum women).

INTERPRETATION: Pregnant and postpartum women face substantial tuberculosis risk, yet remain under-represented in global estimates. Our findings underscore the need for improved surveillance and targeted interventions to reduce tuberculosis incidence in this group.

PMID: 41519136 [Indexed for MEDLINE]

26. Nat Med. 2026 Feb;32(2):553-560. doi: 10.1038/s41591-025-04164-x. Epub 2026 Jan 13.

Discovery and development of a new oxazolidinone with reduced toxicity for the treatment of tuberculosis.

Linezolid, an oxazolidinone, is a cornerstone of treatment regimens for highly drug-resistant tuberculosis but cannot be used in drug-susceptible disease because of toxicity. This toxicity results from inhibition of mammalian mitochondrial protein synthesis. Here we show the development of a new oxazolidinone, MK-7762, with antitubercular activity that is better than linezolid and limited mitochondrial protein synthesis inhibition. The cryogenic electron microscopy structure of the stalled mycobacterial ribosome with MK-7762 revealed the basis for this selectivity. BALB/c mouse models of disease showed MK-7762 reduced lung bacterial burden by a 3-log-fold decrease in an acute model (N = 18) and a 2-log-fold decrease in chronically infected animals (N = 18). MK-7762 showed lesion penetration similar to linezolid in C3HeB/FeJ mice. MK-7762 had pharmacokinetic properties predicting low once-daily doses in humans and a favorable 14-day preclinical safety profile in Wistar Han rats (N = 30) and Beagle dogs (N = 6). Four-month safety studies in both rats (N = 20) and dogs (N = 24) showed no changes in hematology parameters at exposures well above the 100-mg predicted human dose. These data will enable MK-7762 to be explored as a component of new tuberculosis treatment combinations for all forms of the disease.

PMID: 41530381 [Indexed for MEDLINE]

27. Ann Intern Med. 2026 Feb;179(2):187-195. doi: 10.7326/ANNALS-25-00772. Epub 2025 Dec 16.

Diagnostic Follow-up of Positive Results on Low-Dose Computed Tomography Screening in the Medicare Population.

BACKGROUND: Diagnostic evaluation of positive screening results for lung cancer is critically important for optimal outcomes. Data on such follow-up are limited.

OBJECTIVE: To assess the use of diagnostic tests after positive results on lung cancer screening in clinical practice.

DESIGN: Retrospective cohort study.

SETTING: U.S. institutions performing diagnostic follow-up of lung cancer screening, 2015 to 2022.

PARTICIPANTS: Persons with a first positive screening result at age 65 years or older who had Medicare fee-for-service coverage.

MEASUREMENTS: Rates of diagnostic test use (imaging or invasive procedures) within 1 year of an index positive screening result and rates of receiving guideline-concordant follow-up care and of receiving less or more intensive (than guideline-concordant) care. Multiple logistic regression was used to assess factors associated with less or more intensive care.

RESULTS: The cohort consisted of 64 555 persons. The rate of guideline-concordant care was 59.7% overall and increased with increasing Lung-RADS score: 49.2% for a score of 3, 68.6% for 4A, 74.1% for 4B, and 79.5% for 4X. Care was less intensive than recommended in 32.3% of participants, generally decreasing with Lung-RADS score: 39.3% for a score of 3, 24.7% for 4A, 25.9% for 4B, and 20.5% for 4X. Rates of more intensive care, applicable only for scores of 3 and 4A, were 11.5% and 6.7%, respectively. Among participants with Lung-RADS scores of 3 and 4A, non-Hispanic Black persons, those who currently smoked, and those undergoing baseline screening had significantly higher rates of less intensive care. Of all participants, 12.4% had a lung cancer diagnosis within 1 year. Invasive procedures were done in 16.2% of all participants and in 7.3% of those without eventual lung cancer.

LIMITATIONS: The cohort was limited to those in fee-for-service Medicare plans. Information on institutional and patient socioeconomic factors was limited.

CONCLUSION: About 60% of participants had guideline-concordant care, and about one third had less intensive care. Invasive procedure rates in those without cancer were low.

PMID: 41397257 [Indexed for MEDLINE]

28. Nat Biomed Eng. 2026 Feb;10(2):245-258. doi: 10.1038/s41551-025-01463-z. Epub 2025 Jul 30.

CRISPR-GPT for agentic automation of gene-editing experiments.

Performing effective gene-editing experiments requires a deep understanding of both the CRISPR technology and the biological system involved. Meanwhile, despite their versatility and promise, large language models (LLMs) often lack domain-specific knowledge and struggle to accurately solve biological design problems. We present CRISPR-GPT, an LLM agent system to automate and enhance CRISPR-based gene-editing design and data analysis. CRISPR-GPT leverages the reasoning capabilities of LLMs for complex task decomposition, decision-making and interactive human-artificial intelligence (AI) collaboration. This system incorporates domain expertise, retrieval techniques, external tools and a specialized LLM fine tuned with open-forum discussions among scientists. CRISPR-GPT assists users in selecting CRISPR systems, experiment planning, designing guide RNAs, choosing delivery methods, drafting protocols, designing assays and analysing data. We showcase the potential of CRISPR-GPT by knocking out four genes with CRISPR-Cas12a in a human lung adenocarcinoma cell line and epigenetically activating two genes using CRISPR-dCas9 in a human melanoma cell line. CRISPR-GPT enables fully AI-guided gene-editing experiment design and analysis across different modalities, validating its effectiveness as an AI co-pilot in genome engineering.

PMID: 40738974 [Indexed for MEDLINE]

29. Cell. 2026 Feb 5;189(3):832-852.e24. doi: 10.1016/j.cell.2025.11.026. Epub 2025 Dec 19.

Nuclear speckle proteins form intrinsic and MALAT1-dependent microphases.

Pre-mRNA processing components in nuclear speckles encompass one or more folded RNA recognition motifs (RRMs) and disordered regions with specific sequence grammars. Such proteins include serine/arginine-rich splicing factors (SRSFs) and transactive response DNA binding protein (TDP)-43. The SRSFs and TDP-43 are unique archetypes of block copolymers encoding specific patterns of inter-domain homotypic and heterotypic attractions and repulsions. The interplay of these interactions drives microphase separation and the formation of ordered, size-limited assemblies. Microphases of SRSFs and TDP-43 are 23-45 nm in diameter, each comprising tens of molecules. Sub-micron-scale assemblies of SRSFs in cells are consistent with being clusters of microphases. The speckle-associated regulatory long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) binds specifically and preferentially to SRSF1 microphases, while destabilizing TDP-43 microphases. In protein mixtures, the interactions between microphases drive the formation of micron-scale double-emulsion structures with core-shell organization. Our findings show how interactions involving copolymers featuring folded domains and disordered regions drive the formation of microphases.

PMID: 41421357 [Indexed for MEDLINE]

30. Cell Res. 2026 Mar;36(3):197-218. doi: 10.1038/s41422-025-01217-1. Epub 2026 Feb 3.

Dynamic magneto-mechanical force in lysosomes induces durable macrophage repolarization for antitumor immunity.

Mechanical forces are emerging physical cues that regulate biochemical signals of immune cells for antitumor immunity. Owing to the lack of precise tools to impose intracellular forces, little is known about whether and how organelle-level forces trigger mechanotransduction for antitumor immunity. Here, we developed a magneto-mechanical force-triggered lysosomal membrane permeabilization (MagLMP) strategy to induce durable macrophage repolarization for in vivo applications. Self-assembled magnetic nanomotors are driven by rotational magnetic fields, facilitating dynamic damage to the lysosomal membrane by a finely tuned torque-induced vortex. Intriguingly, galectin 9 (Gal9) was found to be critical for sensing cyclic MagLMP, which dynamically activated AMP-activated protein kinase (AMPK), enhanced activation of nuclear factor kappa B (NF-κB), and induced metabolic alterations for sustained M1-like macrophage repolarization, followed by mounting of antitumor immunity. Through single-cell RNA sequencing of tumor tissues, as well as macrophage depletion-reconstitution models involving intratumoral transfer of Gal9-KO bone marrow-derived macrophages (BMDMs) and AMPK shRNA-transduced Gal9-KO BMDMs, we confirmed the Gal9-AMPK-NF-κB axis as the essential pathway by which MagLMP functions in antitumor therapy. In a mouse model of lung adenocarcinoma in situ, overall survival was extended after intravenous administration of nanomotors followed by cyclic MagLMP, and one third of mice survived for more than 300 days. Together, these results demonstrate an intracellular mechanical strategy that can dynamically manipulate innate immune responses in vivo, providing a tool for durable immunotherapy through organelle mechanotransduction.

PMID: 41629559 [Indexed for MEDLINE]

31. J Clin Oncol. 2026 Feb 13:JCO2501892. doi: 10.1200/JCO-25-01892. Online ahead of print.

Medicaid Expansion and Stage at Diagnosis, Timely Initiation and Receipt of Guideline-Concordant Treatment, and Survival Among People With Non-Small Cell Lung Cancer.

PURPOSE: To examine the associations between Medicaid expansion and stage at diagnosis, timely initiation and receipt of guideline-concordant treatment, and 5-year overall survival (OS) among people with non-small cell lung cancer (NSCLC).

METHODS: Individuals newly diagnosed with stage I to IV NSCLC at age 18-64 years between January 1, 2004, and December 31, 2023, in 50 states and Washington, DC, were identified from the National Cancer Database. We examined the association of Medicaid expansion and (1) early-stage diagnosis (I and II); (2) timely initiation of guideline-concordant treatment within 30 days after diagnosis; (3) receipt of all first-course guideline-concordant treatment; and (4) 5-year OS. We applied conventional and updated (Sun and Abraham) difference-in-differences (DID) approaches to examine the changes in study outcomes associated with Medicaid expansion using multivariable linear probability models to estimate stage and treatment and multivariable flexible parametric survival models to investigate survival overall and by key factors.

RESULTS: Compared with people in nonexpansion states (n = 164,228), people in expansion states (n = 350,290) were more likely to be female, non-Hispanic White, or living in areas with higher family income or in nonmetropolitan areas. Medicaid expansion was associated with increases in early-stage NSCLC diagnosis (DID: 1.02 percentage points [ppt; 95% CI, 0.52 to 1.52]), timely treatment initiation (2.10 ppt [95% CI, 0.05 to 4.15]), and higher 5-year OS (1.79 ppt [95% CI, 1.32 to 2.26]). In stratified analyses, people living in areas with lower household income were more likely to benefit from Medicaid expansion.

CONCLUSION: Medicaid expansion was associated with improvements in early detection, timeliness of guideline-concordant treatment, and survival for people with NSCLC. Anticipated Medicaid coverage losses may jeopardize these gains.

PMID: 41687045

32. Cancer Discov. 2026 Feb 6;16(2):391-411. doi: 10.1158/2159-8290.CD-25-0525.

p53 Drives Lung Cancer Regression through a TSC2/TFEB-dependent Senescence Program.

Pharmacologic restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma. However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. In this study, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in lung adenocarcinoma. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and Transcription factor EB (TFEB) nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent lung adenocarcinoma cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in lung adenocarcinoma and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

SIGNIFICANCE: Cancer therapies based on targeting the p53 pathway remain elusive. To address this gap, we unravel the detailed sequence of events governing p53-induced tumor regression in lung adenocarcinoma. These analyses reveal a TSC2-mTORC1-TFEB axis underlying p53-driven senescence and tumor regression, which suggests new strategies to perfect p53-based combination therapies for lung adenocarcinoma.

PMID: 41115251 [Indexed for MEDLINE]

33.Lancet Infect Dis. 2026 Feb 16:S1473-3099(26)00003-4. doi: 10.1016/S1473-3099(26) 000 03-4. Online ahead of print.

The looming crisis of bedaquiline-resistant tuberculosis and a promising way forward.

Drug-resistant tuberculosis is entering a new and dangerous phase. Bedaquiline and other newer drugs have transformed drug-resistant tuberculosis treatment, yet resistance to these agents is now being reported across high-burden settings. In some regions, baseline bedaquiline resistance is substantial, treatment outcomes for extensively drug-resistant tuberculosis remain poor and mortality is unacceptably high. At the same time, the tuberculosis drug pipeline is stronger than it has been in decades, with several promising investigational compounds advancing to late-stage trials. However, regulatory approval remains years away, leaving people with few or no effective treatment options to wait-and often die-while drugs with potential benefit remain inaccessible. Here, we argue that the central barrier to addressing complex drug-resistant tuberculosis is not scientific, but moral and organisational. Drawing on lessons from earlier pre-approval access programmes for bedaquiline and delamanid, we propose the establishment of compassionate-use support platforms (CUSPs): coordinated, global mechanisms to facilitate equitable access to investigational tuberculosis drugs before formal approval. Well designed CUSPs could balance urgency with safety, share responsibility across stakeholders, strengthen diagnostic and pharmacovigilance capacity, and ensure that people with the most difficult-to-treat tuberculosis are not excluded from scientific progress.

PMID: 41713477

34.J Clin Oncol. 2026 Mar;44(7):e56-e88. doi: 10.1200/JCO-25-02825. Epub 2026 Feb 3.

Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, 2026.3.0.

PURPOSE: To provide evidence-based recommendations for patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations.

METHODS: This ASCO living guideline offers continually updated recommendations based on an ongoing systematic review of randomized controlled trials (RCTs), with the latest time frame spanning March-October 2025. An Expert Panel of medical oncology, pulmonary, community oncology, research methodology, and advocacy experts was convened. The literature search included systematic reviews, meta-analyses, and RCTs. Outcomes of interest include efficacy and safety. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations.

RESULTS: This guideline consolidates all previous updates and reflects the body of evidence informing this guideline topic. Six new RCTs were identified in the latest search of the literature to date.

RECOMMENDATIONS: Evidence-based recommendations were updated to address first, second, and subsequent treatment options for patients without driver alterations.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

PMID: 41632927

35. Nat Med. 2026 Feb 2. doi: 10.1038/s41591-025-04181-w. Online ahead of print.

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: 4162942