PubMed：

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

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

1. Nat Med. 2026 Jan;32(1):231-244. doe: 10.1038/s41591-025-04060-4. Pub 2026 Jan 5.

AI-enabled virtual spatial proteomics from histopathology for interpretable biomarker discovery in lung cancer.

Spatial proteomics enables high-resolution mapping of protein expression and can transform our understanding of biology and disease. However, major challenges remain for clinical translation, including cost, complexity and scalability. Here we present H&E to protein expression (HEX), an AI model designed to computationally generate spatial proteomics profiles from standard histopathology slides. Trained and validated on 819,000 histopathology image tiles with matched protein expression from 382 tumor samples, HEX accurately predicts the expression of 40 biomarkers encompassing immune, structural and functional programs. HEX demonstrates substantial performance gains over alternative methods for protein expression prediction from H&E images. We develop a multimodal data integration approach that combines the original H&E image and AI-derived virtual spatial proteomics to enhance outcome prediction. Applied to six independent non-small-cell lung cancer cohorts totaling 2,298 patients, HEX-enabled multimodal integration improved prognostic accuracy by 22% and immunotherapy response prediction by 24-39% compared with conventional clinic pathological and molecular biomarkers. Biological interpretation revealed spatially organized tumor-immune niches predictive of therapeutic response, including the co-localization of T helper cells and cytotoxic T cells in responders, and immunosuppressive tumor-associated macrophage and neutrophil aggregates in non-responders. HEX provides a low-cost and scalable approach to study spatial biology and enables the discovery and clinical translation of interpretable biomarkers for precision medicine.

PMID: 41491099 [Indexed for MEDLINE]

2. Nat Med. 2026 Jan 7. doe: 10.1038/s41591-025-04097-5. Online ahead of print.

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

3. Clan Microbial Rev. 2026 Jan 7: e0019425. doe: 10.1128/cmr.00194-25. Online ahead of print.

The power of resistance: mechanisms of antimicrobial resistance in Mycobacterium tuberculosis and its impact on tuberculosis management.

SUMMARY：The global resurgence of drug-resistant tuberculosis (DR-TB) presents a formidable challenge to public health, driven by a complex interplay of mycobacterial evolution, dynamics and outcomes of host-pathogen interactions and systemic gaps in diagnosis and treatment strategies. This comprehensive review delineates the multifactorial basis of antimicrobial resistance (AMR) in Mycobacterium tuberculosis (MT), integrating molecular, immunological, and pharmacological perspectives to inform next-generation strategies for effective TB control. We conceptualize TB as a dynamic clinical spectrum-ranging from asymptomatic infection to overt disease-shaped by granuloma biology and bacterial adaptation. This spectrum underpins both diagnostic ambiguity and therapeutic failure, particularly in the context of phenotypic drug tolerance/resistance to current anti-TB drugs. We discuss MT’s intrinsic and extrinsic resistance mechanisms, including the lipid-rich cell envelope, efflux systems, and enzymatic drug modification, which are compounded by acquired mutations that disrupt drug activation, alter targets, and confer cross-resistance. These adaptations are further potentiated by granuloma-induced pharmacokinetic heterogeneity and host-induced metabolic quiescence. We highlight the emerging role of therapeutic drug monitoring and pharmacokinetic/pharmacodynamics modeling in optimizing individualized therapy, particularly for novel regimens incorporating bed aquiline, pretomanid, and linezolid. Moreover, we underscore the diagnostic limitations in detecting heteroresistance and early-stage disease, advocating for expanded deployment of advanced and targeted molecular diagnostic modalities. Finally, we propose a paradigm shift toward integrated, precision-based TB management, leveraging host-directed therapies, biofilm-disrupting agents, and real-time pharmacokinetics-guided dosing to preempt resistance emergence and improve clinical outcomes. This review provides a translational framework for addressing the biological and operational complexities of DR-TB in the era of AMR.

PMID: 41498549

4. Nature. 2026 Jan 21. doi: 10.1038/s41586-025-09985-x. Online ahead of print.

Critical role for a high-plasticity cell state in lung cancer.

Plasticity-the ability of cells to undergo phenotypic transitions-drives cancer progression and therapy resistance1-3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4-6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between

cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.

PMID: 41565826

5. Nat Med. 2026 Jan 13. doi: 10.1038/s41591-025-04164-x. Online ahead of print.

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

6. CA Cancer J Clin. 2026 Jan-Feb;76(1):e70043. doi: 10.3322/caac.70043.

Cancer statistics, 2026.

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using data collected by central cancer registries (incidence, through 2022) and the National Center for Health Statistics (mortality, through 2023). In 2026, approximately 2,114,850 new cancer cases and 626,140 cancer deaths are projected to occur in the United States. The cancer mortality rate continued to decline through 2023, averting 4.8 million deaths since 1991, largely because of smoking reductions, earlier detection, and improved treatment. These interventions are also evident in rising 5-year relative survival, which reached a milestone 70% for diagnoses during 2015-2021 overall, 69% for regional-stage disease, and 35% for distant-stage (metastatic) disease, up from 63%, 54%, and 17%, respectively, in the mid-1990s. People with high-mortality cancers and advanced diagnoses had the largest gains, including increases from 32% to 62% for myeloma, 7% to 22% for liver cancer, 16% to 35% for metastatic melanoma, 8% to 18% for metastatic rectal cancer, 20% to 37% for regional lung cancer, and 2% to 10% for metastatic lung cancer. Nevertheless, lung cancer will cause more deaths in 2026 than second-ranking colorectal cancer and third-ranking pancreatic cancer combined.

In summary, decades of scientific investment have translated to longer lives for people with even the most fatal cancers. However, continued progress is threatened by proposed federal cuts to cancer research and health insurance, which provides access to life-saving cancer treatment.

PMID: 41528114 [Indexed for MEDLINE]

7. Lancet Infect Dis. 2026 Jan 28:S1473-3099(25)00747-9. doi: 10.1016/S1473-3099(25)00747-9. Online ahead of print.

Immediate or high-dose antituberculosis therapy for HIV-related sepsis in Tanzania and Uganda (ATLAS): a phase 3, open-label, randomised, controlled, 2 × 2 factorial, superiority trial.

BACKGROUND: People living with HIV and hospitalised with sepsis in Africa are at

risk of death due to tuberculosis but diagnostics for tuberculosis might be delayed or inaccessible for people presenting for critical care. We aimed to compare the effects of immediate empirical and high-dose antituberculosis therapy on 28-day mortality in adult people living with HIV with sepsis in east Africa.

METHODS: ATLAS was a phase 3, open-label, randomised, controlled, 2 × 2 factorial, superiority trial conducted at four hospitals in Tanzania and Uganda. Participants were aged 18 years or older, living with HIV, and had been admitted to hospital with sepsis with two or more modified quick Sequential Organ Failure Assessment score criteria. Exclusion criteria were active tuberculosis or receipt of antituberculosis therapy within 6 months of hospitalisation, pregnancy or lactation, allergies to antituberculosis therapy, another investigational drug within the past month, chronic liver disease, heavy alcohol

use, positive serum cryptococcal antigen, or anticipated significant drug-drug interaction with rifampicin. A computer-generated permuted-block algorithm with allocation concealment and random block sizes of four and eight randomly assigned participants (1:1) to receive either immediate or diagnosis-dependent antituberculosis therapy, and (1:1) to receive either high-dose or conventional WHO-recommended weight-based dose antituberculosis therapy. Allocation was stratified by country and the presence of altered mental status at the time of randomisation. Participants randomly assigned to conventional-dose antituberculosis therapy received fixed-dose combination tablets of rifampicin approximately 10 mg/kg, isoniazid approximately 5 mg/kg, pyrazinamide, and ethambutol, plus pyridoxine 50 mg orally. Participants randomly assigned to receive high-dose antituberculosis therapy received rifampicin approximately 30 mg/kg and isoniazid approximately 7·5 mg/kg as a combination of single formulation tablets and fixed-dose combination tablets that included WHO-recommended weight-based doses of pyrazinamide and ethambutol, plus pyridoxine. Participants continued immediate antituberculosis therapy for 28 days. All medications were administered daily. Participants in the diagnosis-dependent antituberculosis therapy groups received treatment based on a clinical or microbiological diagnosis of tuberculosis. All participants received 2 g intravenous ceftriaxone daily for 7 days. The primary endpoint was 28-day mortality analysed in the modified intention-to-treat population and in the subgroup with later confirmed tuberculosis. We defined the survival time for each participant as the time from randomisation until death, discharged (alive) by day 28, or censored (alive) at day 28. We graded adverse events according to recommendations from the National Institutes of Health Division of AIDS. This study was registered with ClinicalTrials.gov, NCT04618198, and is completed.

FINDINGS: Between Jan 5, 2022, and Dec 9, 2024, 707 people were screened for

eligibility and 437 were randomly assigned (110 to immediate conventional-dose, 112 to immediate high-dose, 107 to diagnosis-dependent conventional-dose, and 108 to diagnosis-dependent high-dose antituberculosis therapy). 395 patients (226 [57%] of whom were female and 169 [43%] were male; all participants were Black) received study intervention and were analysed for the primary outcome of 28-day mortality. We confirmed tuberculosis in 204 (52%) patients. There was no evidence of differences in 28-day mortality in immediate antituberculosis therapy groups (50 deaths [25%] in 198 patients) compared with diagnosis-dependent groups (50 deaths [25%] in 197 patients; adjusted hazard ratio [aHR] 0·99 [95% CI 0·67-1·46]; p=0·95), or in high-dose antituberculosis therapy groups (51 deaths [26%] in 199 patients) compared with conventional-dose groups (49 deaths [25%] in 196 patients; aHR 1·07 [0·72-1·59]; p=0·73). In patients with microbiologically confirmed tuberculosis, the 28-day mortality relative to the diagnosis-dependent conventional-dose group (18 deaths [34%] in 53 patients) was lower for the immediate conventional-dose group (six deaths [12%] in 51 participants; aHR 0·32 [95% CI 0·13-0·82]; p=0·015); for the diagnosis-dependent high-dose group (11 deaths [20%] in 56 patients) was 0·51 (0·24-1·08; p=0·79); and for the immediate high-dose group (11 deaths [26%] in 43 patients) was 0·63 (0·29-1·36; p=0·24). No significant differences in adverse events occurred between treatment groups but numerically more events of drug-induced liver injury occurred in the immediate high-dose group compared with any other group.

INTERPRETATION: Among all participants with HIV-related sepsis, 28-day mortality was not significantly reduced with immediate or high-dose antituberculosis therapy. In the subgroup with later confirmed tuberculosis, immediate conventional-dose antituberculosis therapy significantly reduced 28-day mortality, suggesting, as in other forms of bacterial sepsis, that hours to active treatment might determine survival.

FUNDING: US National Institutes of Health.

PMID: 41619753

8. Nat Cell Biol. 2026 Jan 7. doi: 10.1038/s41556-025-01840-5. Online ahead of print.

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

9. Cancer Cell. 2026 Jan 22:S1535-6108(25)00555-0. doi:10.1016/j.ccell. 2025.12.021.Online ahead of print.

Armored macrophage-targeted CAR-T cells reset and reprogram the tumor microenvironment and control metastatic cancer growth.

Tumor-associated macrophages (TAMs), which commonly express FOLR2 or TREM2, are enriched in solid tumors and keep the tumor microenvironment (TME) immunosuppressed. Here, we introduce IL-12-expressing CAR-T cells targeting FOLR2 or TREM2 to deplete pro-tumor TAMs and reprogram the TME. Treatment with IL-12-armored anti-TAM CAR-T leads to significantly improved survival in metastatic ovarian and lung cancer models. The CAR-T mediates benefit at low cell dose and without lymphodepletion, and remains largely restricted to tumors with no overt toxicity. Spatial transcriptomics reveals that IL-12 anti-TAM CAR-T mediates sustained remodeling of the TME, even after CAR-T contraction, with the expansion of CXCL9+ immunostimulatory macrophages and endogenous tumor-specific cytotoxic T cells. Tumor clearance depends, in part, on FAS expression on cancer cells, revealing an IL-12-FAS axis for IL-12-armored CAR-T activity. These findings position IL-12-producing, myeloid-directed CAR-T as a broad strategy to remodel the TME and drive anti-tumor immunity for solid cancers.

PMID: 41576929

10. Ann Oncol. 2025 Dec 30:S0923-7534(25)06329-X.doi10.1016/j.annonc. 2025.12.011. Online ahead of print.

PET/CT-guided management of immune checkpoint blockade and multi-modal profiling following treatment in long-term responders with metastatic lung cancer in the National Network Genomic Medicine Lung Cancer Germany (nNGM).

BACKGROUND: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases health care burden, exposes patients to avoidable toxicities, and is not supported by any clinical or biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed.

PATIENTS AND METHODS: In this retrospective cohort study, 455 patients from 21 National Network Genomic Medicine Lung Cancer Germany (nNGM) centers with ≥2 years of disease control on first-line ICB-based therapy were grouped into PET/CT-guided discontinuation (cohort A, n = 126) or continued ICB without PET/CT (cohort B, n = 329), and assessed for overall survival (OS). Matched pre- and post-ICB tumor samples from cohort A patients with persistent or progressive disease were analyzed by comprehensive genomic profiling, histological tumor-infiltrating lymphocyte quantification, and spatial transcriptomics to explore mechanisms of late resistance.

RESULTS: After a median follow-up of 55 months, cohort A showed significantly longer OS [median not reached versus 82 months, hazard ratio 0.35 (95% confidence interval 0.18-0.67), P = 0.002], despite substantially shorter treatment duration (27 versus 45 months, P < 0.001). Discontinuation was either PET-driven (A) or resulted from immune-related toxicity, progression, or patients' choice (B). Systematic re-biopsies in cohort A revealed a high incidence of second primary lung cancers (SPLC, 28%). All progression events were managed exclusively with local (ablative) treatments in 53% (A) versus 17% (B). Tumors that occurred after treatment exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low programmed death ligand 1 expression, low tumor mutational burden, and immunologically cold tumor microenvironments.

CONCLUSIONS: A structured discontinuation strategy appears to provide a safe approach for long-term ICB responders, enabling earlier detection of resistance before generalized progression. A confirmatory prospective non-inferiority randomized trial within the nNGM is underway.

PMID: 41478526

11. Lancet Glob Health. 2026 Jan 7:S2214-109X(25)00431-0. doi: 10.1016/S2214-109X(25)00431-0. Online ahead of print.

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

12. Science. 2026 Jan 15:eadz9353. doi: 10.1126/science.adz9353. Online ahead of print.

A genetically encoded device for transcriptome storage in mammalian cells.

Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes. We present TimeVault, a genetically encoded system that records and stores transcriptomes within living mammalian cells for future readout. TimeVault leverages engineered vault particles that capture mRNA through poly(A) binding protein. We demonstrate that the transcriptome stored by TimeVaults is stable in living cells for over 7 days. TimeVault enables high-fidelity transcriptome-wide recording with minimal cellular perturbation, capturing transient stress responses and revealing gene expression changes underlying drug-naive persister states in lung cancer cells that evade EGFR inhibition. By linking past and present cellular states, TimeVault provides a powerful tool for decoding how cells respond to stress, make fate decisions, and resist therapy.

PMID: 41538410

13. Nat Rev Clin Oncol. 2026 Jan 7. doi: 10.1038/s41571-025-01112-z. Online ahead of print.

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

14. Cancer Discov. 2026 Jan 14. doi: 10.1158/2159-8290.CD-25-1483. Online ahead of print.

Circulating Tumor Cells Predict Response to the DLL3-targeting Bispecific  Antibody Tarlatamab.

The bispecific antibody tarlatamab recruits T cells to cancers expressing the neuroendocrine epitope DLL3. Tarlatamab is effective in small cell lung cancer (SCLC), but clinical outcomes vary, and no biomarkers enable patient selection. Single-cell RNA sequencing of SCLC biopsies identifies heterogeneity in DLL3 expression, and analysis of circulating tumor cells (CTCs) distinguishes individual patients as predominantly DLL3Pos or DLL3Low. In a prospective cohort of 20 patients, pretreatment DLL3 expression on CTCs predicts tarlatamab clinical benefit (85% sensitivity, 100% specificity). Necrotic CTC clusters in blood accompany treatment-induced tumor lysis. Acquired resistance to tarlatamab is associated in some cases with loss of DLL3 expression, but persistence of other targetable neuro-endocrine epitopes; in other patients, DLL3 is retained on CTCs, but accompanied by systemic markers of T cell dysfunction. Quantitation of DLL3-positive CTCs identifies patients likely to benefit from tarlatamab, and longitudinal monitoring may guide therapeutic decision-making at the time of acquired resistance.

PMID: 41532856

15. JAMA Oncol. 2026 Jan 22. doi: 10.1001/jamaoncol.2025.6080. Online ahead of print.

Cost-Effectiveness of Adjuvant Immunotherapy in Cancer Treatments: A Systematic Review.

IMPORTANCE: Adjuvant immunotherapy is increasingly integrated into cancer care to reduce recurrence and improve survival. However, its high cost raises critical concerns regarding affordability and economic value across diverse health system contexts.

OBJECTIVE: To synthesize published economic evaluations of adjuvant immunotherapy and assess cost-effectiveness outcomes, quality-adjusted life-year (QALY)/life-year (LY) gains, and methodologic approaches.

EVIDENCE REVIEW: A systematic search was conducted of PubMed, Scopus, Embase, and Web of Science for full economic evaluations published between January 1, 2015, and January 31, 2025. Eligible studies included cost-effectiveness or cost-utility analyses of adjuvant immunotherapy across any cancer type. Data were extracted on cancer type, treatment strategy (single vs combination therapy), treatment line, model structure, health utility instruments, funding sources, and cost-effectiveness outcomes. Methodologic quality was appraised using the Criteria for Health Economic Quality Evaluation 2023. Due to heterogeneity of health systems, findings were narratively synthesized.

FINDINGS: The analysis included 69 studies covering a range of cancer types, most frequently non-small cell lung cancer and melanoma. Of these, 46 (67%) evaluated first-line therapy with single-agent checkpoint inhibitors. Higher QALY/LY gains were consistently reported among the adjuvant immunotherapy group (63 [91%]), particularly for non-small cell lung cancer, industry-funded studies, and combination regimens. More than half of the evaluations (40 [58%]) concluded that adjuvant immunotherapy was cost-effective, although results varied by cancer type, model assumptions, drug pricing, funding organizations, and country-specific thresholds. Markov modeling was the dominant analytic approach (46 [67%]) and EuroQol 5 Dimensions was the most commonly used health utility instrument (56 [81%]).

CONCLUSIONS AND RELEVANCE: This systematic review found that adjuvant immunotherapy was frequently associated with meaningful QALY/LY improvements and was often considered cost-effective in high-risk or first-line settings. However, economic value remains context-specific, shaped by treatment strategy, drug costs, and modeling assumptions. These findings support the selective, value-based adoption of adjuvant immunotherapy and underscore the need for transparent, standardized economic evaluations to guide reimbursement and policy decisions.

PMID: 41569596

16. Cancer Discov. 2026 Jan 21. doi: 10.1158/2159-8290.CD-25-1346. Online ahead of print.

Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRAS G12D Inhibitor.

KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRAS G12D inhibitor that inhibits proliferation of KRAS G12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune check blockade (ICB). In a Phase 1a study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung cancer (NSCLC), the objective response rate (ORR, unconfirmed) is 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC) the ORR (unconfirmed) was 33.33% in the 1000-1200mg cohort. This study supports the clinical potential of RNK08954 in patients with KRAS G12D mutation either as a single agent or in combination.

PMID: 41557983

17. Nature. 2026 Jan;649(8096):487-495. doi: 10.1038/s41586-025-09710-8. Online ahead of print.

Targeting FSP1 triggers ferroptosis in lung cancer.

Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1-3. Despite broad enthu-siasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown 4,5. Here, using genetically engineered mouse models of lung adenocar-cinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppress-ors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.

PMID: 41193800 [Indexed for MEDLINE]

18. J Clin Oncol. 2026 Jan 13:JCO2501828. doi: 10.1200/JCO-25-01828. Online ahead of print.

Adjuvant Durvalumab in Completely Resected Early-Stage Non-Small Cell Lung Cancer.

PURPOSE: Adjuvant immunotherapy improved patient outcomes in two trials in completely resected non-small cell lung cancer (NSCLC), but with conflicting primary end point results. The Canadian Cancer Trials Group BR.31 trial evaluated adjuvant durvalumab in completely resected early-stage NSCLC.

METHODS: Following resection of stage IB (≥4 cm) to IIIA NSCLC (American Joint Committee on Cancer 7th Edition) and optional adjuvant chemotherapy, patients were randomly assigned 2:1 to durvalumab 20 mg/kg or placebo 20 mg/kg once every 4 weeks for 12 cycles. Random assignment was stratified by stage, extent of nodal dissection, tumor cell (TC) PD-L1 expression, adjuvant chemotherapy use, and center. The primary end point was investigator-assessed disease-free survival (DFS). Secondary outcomes included overall survival (OS), adverse events, and quality of life. The primary analysis was in the subgroup with cancers that had a PD-L1 TC expression ≥25%, no common activating EGFR mutations (EGFR-), and no ALK gene rearrangements (ALK-). Secondary analyses in hierarchical order included DFS in the subgroup whose tumors were EGFR-/ALK- with PD-L1 TC ≥1%, followed by all patients whose tumors were EGFR-/ALK-, followed by OS in the same primary and secondary subgroups in the same hierarchical order.

RESULTS: Of 1,415 patients randomly assigned, 1,219 (86%) had EGFR-/ALK- tumors: 815 randomly assigned to durvalumab and 404 to placebo. With a median follow-up of 60 months, there were no differences in DFS between patients assigned durvalumab (316) versus placebo (161) in the primary population (stratified hazard ratio [HR], 0.93 [95% CI, 0.71 to 1.25]; P = .64) or in the secondary populations. Grade 3 to 4 adverse events were higher in durvalumab-treated patients (D = 26% v P = 20%).

CONCLUSION: Adjuvant durvalumab following complete resection was not associated with improvement in DFS compared with placebo in EGFR-/ALK- NSCLC, regardless of PD-L1 status.

PMID: 41529222

19. Nat Med. 2026 Jan 28. doi: 10.1038/s41591-025-04186-5. Online ahead of print.

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

20. Cancer Discov. 2026 Jan 13. doi: 10.1158/2159-8290.CD-25-1222. Online ahead of print.

PD1 blockade-induced DKK1 expression by CD8+ T cells promotes blood-brain barrier permeabilization.

Anti-PD1 therapy benefits a subset of brain metastasis (BrM) patients; however, heterogeneous responses imply an incomplete understanding of the brain-immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. While anti-PD1 induced robust anti-tumor immune activation, it uniquely, among all ICIs tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8⁺ T cells through the induction of β-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma-DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, lung cancer patients receiving anti-PD1 exhibited increased MRI contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in non-responders. Sequencing anti-PD1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD1-induced BBB modulation as a tractable vulnerability in BrM management.

PMID: 41525686

21. J Clin Oncol. 2026 Jan 28:JCO2501546. doi: 10.1200/JCO-25-01546. Online ahead

of print.

Efficacy and Safety of Ultra-Low-Dose Immunotherapy in Relapsed Refractory Solid Tumors: Phase III Superiority Randomized Trial (DELII).

PURPOSE: Immune checkpoint inhibitors (ICIs) achieve sufficient receptor occupancy at much lower than standard approved doses. We hypothesized that ultra-low-dose nivolumab would retain clinical efficacy.

PATIENTS AND METHODS:  In this phase III randomized superiority trial, patients with advanced solid tumors (Eastern Cooperative Oncology Group 0-1) and progression on ≥1 prior line of systemic therapy were randomly assigned 1:1 to ultra-low-dose nivolumab (20 mg intravenously once every 2 weeks) or standard chemotherapy (docetaxel or paclitaxel, as per tumor type). Treatment continued until progression or intolerable toxicity. The primary end point was overall survival (OS).

RESULTS: From June 2020 to February 2024, we enrolled 500 patients: 250 per arm; 52% had head and neck and 36% lung cancers. The median number of prior lines of therapy was 1 (range, 1-8); 29% had received ≥2 prior lines. Median OS was significantly longer with ultra-low-dose nivolumab: 5.88 months (95% CI, 4.99 to 7.13) versus 4.70 months (95% CI, 3.91 to 5.65; hazard ratio [HR], 0.80 [95% CI, 0.66 to 0.97]; P = .022). One-year OS was 27.3% versus 16.9%. Median progression-free survival was similar: 2.04 months (95% CI, 2.00 to 2.10) with ultra-low-dose nivolumab and 2.09 months (95% CI, 2.04 to 2.17) with chemotherapy (HR, 1.03 [95% CI, 0.86 to 1.23]; P = .77). Grade ≥3 treatment-related adverse events were less frequent with ultra-low-dose nivolumab (42.5% v 60.8%; P < .001). Quality of life (QoL) was significantly better with ultra-low-dose nivolumab.

CONCLUSION: Ultra-low-dose nivolumab significantly improves OS versus chemotherapy in pretreated solid tumors, with fewer severe toxicities and better QoL. These findings support re-evaluation of ICI dosing strategies and may enhance global access.

PMID: 41604598

22. Nat Med. 2026 Jan 6. doi: 10.1038/s41591-025-04086-8. Online ahead of print.

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

23. Cancer Cell. 2026 Jan 12;44(1):187-202.e7. doi: 10.1016/j.ccell.2025.09.011.

Online ahead of print.

TET2-mutant clonal hematopoiesis enhances macrophage antigen presentation and improves immune checkpoint therapy in solid tumors.

Clonal hematopoiesis (CH) is detectable in upwards of 20% of patients with solid tumors and is associated with worsened prognosis; however, its role in tumor immu-neology and immune checkpoint therapy (ICT) is unknown. Using a bone marrow  chimera model of Tet2+/mut CH in mice with solid tumors, we found the Tet2-mutant myeloid cells are abundant in the tumor microenvironment and contributed to an improved response to ICT. Mechanistically, Tet2+/mut macrophages inside the tumor act as immunogenic antigen-presenting cells that more effectively cross-prime naive CD8+ T cells in response to IFNγ. In human cohorts of 35,971 non-small cell lung cancer patients and 25,064 colorectal adenocarcinoma patients, TET2-mutant CH is associated with improved outcome specifically with ICT. This study proposes a role for Tet2+/mut antigen presenting macrophages in shaping antitumor immunity and identifies TET2-mutant CH as a potential biomarker for improved response to ICT in patients with solid tumors.

PMID: 41106379 [Indexed for MEDLINE]

24. Lancet Infect Dis. 2026 Feb;26(2):203-212. doi: 10.1016/S1473-3099(25)00536-5. Online ahead of print.

Long-term risk of tuberculosis among individuals with Xpert Ultra trace screening results in Uganda: a longitudinal follow-up study.

BACKGROUND: Systematic screening for tuberculosis using Xpert Ultra can generate trace results of uncertain significance. Additional microbiological testing in this context is often negative, but untreated individuals might still progress to culture-positive disease. We aimed to estimate the 2-year risk of tuberculosis among screened participants with trace-positive sputum (PWTS).

METHODS: In this longitudinal follow-up study, we conducted Ultra-based systematic screening for tuberculosis in Kampala, Uganda, from Feb 2, 2021, to April 27, 2024, enrolling PWTS as well as participants who were Ultra-positive or Ultra-negative controls. Recruitment occurred primarily through community-based screening events and door-to-door screening. Ultra sputum testing was offered to individuals aged 15 years or older who were not on active tuberculosis treatment, regardless of their symptoms. All PWTS, as well as age-matched and sex-matched participants with negative screening results and consecutive participants with positive screening results, were recruited. Participants underwent extensive initial evaluation, and untreated PWTS and negative-control participants were followed up with re-testing for up to 24  months. Our primary outcome was the cumulative hazard of tuberculosis among PWTS, using two definitions of tuberculosis: one incorporating clinician judgement and one strictly microbiological. We then compared hazards between PWTS and negative-control participants. We also assessed whether the presence of symptoms or chest x-ray abnormalities at baseline were associated with tuberculosis diagnosis during follow-up in PWTS.

FINDINGS: We screened 31 505 people for tuberculosis in Uganda using sputum Xpert Ultra as an initial test through event-based and door-to-door screening. We enrolled 128 PWTS and 139 age-matched and sex-matched control participants who were Ultra-negative (negative-control participants) into prospective cohorts and 110 control participants who were Ultra-positive (more than trace) for cross-sectional comparison. Of 128 PWTS, 79 (62%) were male, 49 (38%) were female, and 19 (15%) were HIV positive; 45 (35%) were recommended for treatment upon enrolment, eight (6%) were lost to follow-up within 3 months, and 75 (56%) were followed up for a median of 706 days (IQR 344-714), of whom 19 (25%) were recommended for treatment during follow-up. The cumulative hazard of tuberculosis among PWTS not treated at baseline was 0·24 (95% CI 0·15-0·40) at 1 year and 0·33 (0·21-0·54) at 2 years, versus 0·03 (0·01-0·10) at 2 years for negative-control participants. Hazards were similar for microbiologically defined tuberculosis (0·36 [95% CI 0·22-0·58] for PWTS vs 0·02 [0·01-0·10] for negative-control participants at 2 years). Tuberculosis diagnosis during

follow-up was strongly associated with atypical baseline chest x-ray (ie, interpreted by radiologists as having any abnormality; hazard ratio 14·6 [95% CI 3·3-63·8]) but not with baseline symptoms (cough, fever, night sweats, or weight loss).

INTERPRETATION: Individuals with trace-positive sputum during screening have a substantial 2-year risk of tuberculosis, even when extensive initial evaluations do not confirm disease. Treatment should be considered for most screening participants with trace-positive sputum and atypical chest imaging.

PMID: 41072452 [Indexed for MEDLINE]

25. Cancer Cell. 2026 Jan 29:S1535-6108(26)00010-3. doi: 10.1016/j.ccell. 2026.01.001. Online ahead of print.

Emerging landscape of KRAS inhibitors in cancer treatment.

Alterations in KRAS, NRAS, and HRAS occur in roughly 20% of patients with cancer, making RAS one of the most intensively studied oncogenic targets. The discovery of mutant-selective KRASG12C inhibitors has provided a proof-of-concept for RAS-directed therapies, heralding a new era in the treatment of RAS-driven cancers. Yet, the efficacy of first-generation KRASG12C inhibitors is limited by the rapid emergence of resistance. Novel classes of (K)RAS inhibitors with distinct mechanisms of action and broader target coverage hold promise to overcome resistance and extend the benefits of RAS-targeted therapies to a wider patient population. In this review, we summarize clinical evidence for KRASG12C inhibitors across tumor types and delineate key mechanisms of resistance. We further discuss the rapidly evolving landscape of next-generation (K)RAS inhibitors, with particular emphasis on their target selectivity, mechanisms of action, preliminary clinical efficacy, and the therapeutic opportunities and challenges inherent to each class.

PMID: 41616774

26. Adv Sci (Weinh). 2026 Jan 18:e21886. doi: 10.1002/advs.202521886. Online ahead of print.

Fluorinated Hypoxia-Responsive Aza-BODIPY for NIR-II FL/(19)F MR/PA Imaging and Phototherapy of Lung Cancer.

Tumor hypoxia limits the efficacy of photodynamic therapy (PDT), necessitating photosensitizers with hypoxia-adaptive therapy and imaging. Here, we present a fluorinated N-oxide aza-BODIPY (OFBD) nanoemulsion (OFBD-NP) for hypoxia-responsive, multimodal imaging-guided phototherapy. OFBD generates robust singlet oxygen under normoxia for PDT, but is reduced by CYP450 enzymes in hypoxic cells to photothermal-potent FBD, enabling switchable PDT/PTT. Co-assembly with fluorinated oil enhances oxygen delivery, boosts 19F MRI sensitivity, and promotes J-aggregation, shifting fluorescence into the NIR-II window for deep-tissue imaging. The redox conversion also activates photoacoustic signals, enabling responsive tri-modal imaging (NIR-II FLI/19F MRI/PAI). OFBD-NP shows potent cytotoxicity in vitro under both normoxic and hypoxic conditions via apoptosis. In vivo, it selectively accumulates in tumors, offers high-contrast imaging, and leads to complete tumor regression in subcutaneous A549 models after laser irradiation, without systemic toxicity. This work demonstrates a smart nanoplatform that integrates deep-tissue imaging and hypoxia-triggered therapeutic switching, addressing major limitations of conventional photosensitizers in cancer imaging and phototherapy.

PMID: 41549220

27. J Clin Oncol. 2026 Jan 13:JCO2501569. doi: 10.1200/JCO-25-01569. Online ahead of print.

Chemoradiation ± Atezolizumab in Limited-Stage Small Cell Lung Cancer: Results of NRG Oncology/Alliance LU005.

PURPOSE: NRG Oncology/Alliance LU005 (ClinicalTrials.gov identifier: NCT03811002) tested the addition of atezolizumab to concurrent chemoradiation (CRT) in this open-label, phase III international trial.

METHODS: Patients with limited-stage small cell lung cancer (LS-SCLC), stage Tx-IV, N0-3, and M0 with Eastern Cooperative Group performance status (PS) 0-2 received one cycle of chemotherapy (platinum/etoposide) before study registration and were randomly assigned to CRT alone versus CRT plus concurrent and adjuvant atezolizumab, 1,200 mg once daily, every 3 weeks until investigator-assessed progression or intolerable side effects for a maximum of 17 cycles. Patients were stratified by choice of chemotherapy (cisplatin v carboplatin), radiation fractionation schedule (66 Gy once daily v 45 Gy twice daily), sex, and PS (0/1 v 2). The primary end point was overall survival (OS). Secondary end points included investigator-assessed progression-free survival (PFS), objective response rate, local control, and distant-metastasis-free survival (DMFS).

RESULTS: patients were randomly assigned from May 2019 to December 2023. The median OS was 36.1 months (95% CI, 28.1 to 42.5) for the CRT-alone arm and 31.1 months (95% CI, 28.5 to 44.7) for the CRT + atezolizumab arm, respectively (hazard ratio [HR], 1.03 [95% CI, 0.80 to 1.32]). The median PFS was 11.4 months (95% CI, 10.3 to 13.2) for the CRT-alone arm and 12.1 months (95% CI, 10.9 to 15.2) for the CRT + atezolizumab arm, respectively (HR, 0.98 [95% CI, 0.79 to 1.22]). The median DMFS was 13.0 months (95% CI, 11.3 to 18.2) for the CRT-alone arm and 16.8 months (95% CI, 12.1 to 21.6) for the CRT + atezolizumab arm (HR, 0.96 [95% CI, 0.76 to 1.21]). No unexpected safety signals with concurrent atezolizumab were observed.

CONCLUSION: Concurrent and adjuvant atezolizumab with chemoradiation did not improve survival in patients with LS-SCLC.

PMID: 41529214

28. JAMA Oncol. 2026 Jan 1;12(1):84-89. doi: 10.1001/jamaoncol.2025.5097.

Lorlatinib in Tyrosine Kinase Inhibitor-Naive Advanced ROS1-Positive Non-Small Cell Lung Cancer: A Phase 2 Nonrandomized Clinical Trial.

IMPORTANCE: ROS1 rearrangement is rare but is an attractive therapeutic target in advanced non-small cell lung cancer (NSCLC). Crizotinib, entrectinib, and repotrectinib have been approved by the US Food and Drug Administration for treatment of ROS1-positive NSCLC. Lorlatinib, a brain-penetrant, third-generation tyrosine kinase inhibitor (TKI), targets ROS1 and ALK; however, its efficacy and safety for patients with advanced ROS1-positive remains unknown.

OBJECTIVE: To evaluate the efficacy and safety of lorlatinib for patients with advanced ROS1-positive NSCLC never treated with any TKI.DESIGN, SETTING, AND PARTICIPANTS: This multicenter phase 2 nonrandomized clinical trial enrolled patients with advanced ROS1-positive NSCLC who were TKI-naive with an Eastern Cooperative Oncology Group performance status of 2 or less, and 1 or no prior platinum-based chemotherapy. Participants were recruited from June 2019 to April 2023 and followed up through August 2024. Data analysis was performed from April 5 to August 30, 2025.

INTERVENTIONS: Lorlatinib, 100 mg daily, was administered until disease progression, toxic effects, consent withdrawal, or death.

MAIN OUTCOMES AND MEASURES: Objective response rate (ORR). Secondary end points were progression-free survival (PFS), overall survival, and safety.

RESULTS: The analysis included 32 patients (mean [IQR] age, 59 [11] years; 20 female [63%] and 12 male [37%] individuals), all of whom had adenocarcinoma histologic findings. There were 21 patients (66%) who were treatment-naive, and 11 (34%) who had prior chemotherapy. The median (SD) follow-up duration was 22.1 (15.4-46.8) months; ORR was 73% (95% CI, 56%-86%; 22 of 30 patients), and disease control rate was 90% (95% CI, 74%-97%; 27 of 30 patients). Median (IQR) PFS was 53.6 (95% CI, 27.8-79.5) months, and overall survival was not reached. For treatment-naive vs previously treated patients, the ORR was 90% vs 60%, and PFS was not reached vs 35.8 months. Grade 3 to 4 adverse effects were hypertriglyceridemia (5 patients [16%]) and hypercholesterolemia (8 patients [25%]). No treatment-related deaths occurred.

CONCLUSIONS AND RELEVANCE: In this nonrandomized clinical trial, lorlatinib demonstrated durable efficacy and manageable safety in TKI-naive advanced ROS1-positive NSCLC, supporting the potential for using lorlatinib in earlier treatment settings.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03612154.

PMID: 41296331 [Indexed for MEDLINE]

29. Lancet. 2026 Jan 24;407(10526):375-387. doi: 10.1016/S0140-6736(25)01811-2. Epub 2026 Jan 13.

Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): interim analysis of a multicentre, open-label, phase 3 randomised controlled trial.

BACKGROUND: Savolitinib combined with osimertinib is a potential novel therapy for patients with EGFR mutation-positive non-small-cell lung cancer (NSCLC) harbouring MET amplification after progression on EGFR tyrosine kinase inhibitor (TKI) therapy. We aimed to evaluate the efficacy and safety of savolitinib-osimertinib versus standard of care platinum-based doublet chemotherapy in this patient population.

METHODS: SACHI was a multicentre, randomised, active-controlled, open-label, phase 3 trial conducted across 68 Chinese hospitals. Eligible adults with locally advanced or metastatic EGFR mutation-positive NSCLC and MET amplification after EGFR TKI failure were randomly assigned (1:1) to once daily oral savolitinib-osimertinib or intravenous chemotherapy (pemetrexed plus either cisplatin or carboplatin), both in 21-day cycles. Central randomisation was implemented through an interactive web-response system with stratification based on the presence of brain metastases, previous exposure to third-generation EGFR TKIs, and EGFR mutation subtype, using a mixed block-size methodology. The primary endpoint, investigator-assessed progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumours version 1.1, was tested using a hierarchical procedure: first in the third-generation EGFR TKI-naive population, and if positive, the intention-to-treat (ITT) population. Safety analysis was performed in all patients who received at least one dose of the study treatment. Interim analysis data cutoff was Aug 30, 2024. This study is registered with ClinicalTrials.gov (NCT05015608) and is complete.

FINDINGS: Between Oct 15, 2021, and Aug 30, 2024, 211 patients were enrolled, 106 were randomly assigned to savolitinib-osimertinib and 105 were randomly assigned to chemotherapy, including 137 (65%) of 211 who were third-generation EGFR TKI-naive (69 in the savolitinib-osimertinib group; 68 in the chemotherapy group). In 106 patients in the savolitinib-osimertinib group, the median age was 59·4 years (IQR 54·3-65·8), 62 (58%) were female, and 44 (42%) were male. In 105 patients in the chemotherapy group, the median age was 61·9 years (IQR 56·3-69·1), 55 (52%) were female, and 50 (48%) were male. All participants were Asian. Median PFS was significantly prolonged with savolitinib-osimertinib versus chemotherapy in the third-generation EGFR TKI-naive (9·8 months [95% CI 6·9-12·5] vs 5·4 months [4·2-6·0]; hazard ratio 0·34 [0·21-0·56]; p<0·0001) and ITT populations (8·2 months [6·9-11·2] vs 4·5 months [3·0-5·4]; 0·34 [0·23-0·49]; p<0·0001). Grade 3 or worse treatment-emergent adverse events occurred in the same proportion of patients in both groups who received the study drugs (60 [57%] of 106 patients in the savolitinib-osimertinib group and 55 [57%] of 96 patients in the chemotherapy group).

INTERPRETATION: The savolitinib-osimertinib combination improved PFS versus chemotherapy in patients with EGFR mutation-positive, MET-amplified NSCLC that had progressed on EGFR TKI therapy, while maintaining a favourable tolerability profile. This regimen offers a potential oral treatment option for this biomarker-selected population.

PMID: 41544643 [Indexed for MEDLINE]

30. Lancet Oncol. 2026 Jan 12:S1470-2045(25)00643-6. doi: 10.1016/S1470-2045(25)00643-6. Online ahead of print.

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

31. Lancet Infect Dis. 2026 Feb;26(2):e96-e111. doi: 10.1016/S1473-3099(25)00364-0. Epub 2025 Aug 18.

A clinical practice guideline for tuberculous meningitis.

Tuberculous meningitis is the most severe form of tuberculosis, causing death or disability in around half of those affected. There are no up-to-date international guidelines defining its optimal management. Therefore, the Tuberculous Meningitis International Research Consortium conducted a systematic review of available evidence to address key management questions and to develop practice guidance. The consortium includes representatives from India, Indonesia, South Africa, Uganda, Viet Nam, Australia, the Netherlands, the UK, and the USA. Questions were developed using the Population, Intervention, Comparator, Outcome (PICO) format for tuberculous meningitis diagnosis, anti-tuberculosis chemotherapy, adjunctive anti-inflammatory therapy, and neurocritical and neurosurgical care. A Grading of Recommendations, Assessment, Development and Evaluations approach was used to assess the certainty (or quality) of evidence and establish the direction and strength of recommendations for each PICO-based question. We provide evidence-based recommendations for the optimal treatment and diagnosis of tuberculous meningitis, alongside expert opinion. We expose substantial knowledge and evidence gaps, thereby highlighting current research priorities.

PMID: 40840485 [Indexed for MEDLINE]

32. Nat Biomed Eng. 2026 Jan;10(1):69-79. doi: 10.1038/s41551-025-01441-5.

Self-powered rapid antigen-specific T-cell response assay for Mycobacterium tuberculosis infections.

Interferon-gamma release assays (IGRAs) that evaluate an individual's T-cell activation response to Mycobacterium tuberculosis (M.tb)-specific peptides serve an important role in diagnosing tuberculosis (TB). However, there are substantial challenges to the use of IGRAs in resource-limited settings. Further, IGRA diagnostic performance can also be compromised in anergic individuals. Here we describe a microfluidic chip-based antigen-specific T-cell response assay (ASTRA) that automates the detection of M.tb-specific T-cell activation responses to facilitate screening for latent M.tb infection and TB. We observe that ASTRA demonstrates high specificity for M.tb infection in independent patient cohorts. Compared with IGRA, ASTRA shows greater diagnostic sensitivity in individuals with HIV-1 co-infections (93.8% versus 67%), comparable diagnostic sensitivity in HIV-negative individuals (92.8%) and faster detection (4 h versus 24-48 h). We also find that a self-powered ASTRA chip that analysed microsample (~25 μl) whole-blood samples produced comparable results. ASTRA holds the potential to facilitate efforts to control the global TB epidemic and serve as a versatile platform for analysing T-cell responses across various infectious diseases and immunotherapeutic interventions.

PMID: 40579486 [Indexed for MEDLINE]

33. JAMA Oncol. 2026 Jan 15:e255924. doi: 10.1001/jamaoncol.2025.5924. Online ahead of print.

Lymph Node Dissection Guideline Adherence and Survival in Patients With T1N0M0

Lung Adenocarcinoma.

IMPORTANCE: Lymph node dissection for early-stage lung adenocarcinoma is controversial. Histologic pattern subtyping reveals heterogeneity of lung adenocarcinoma, yet its association with lymph node involvement and dissection is understudied.

OBJECTIVE: To assess the association between guideline-adherent lymph node dissection, histologic pattern subtyping, and overall survival in patients with clinical T1N0M0 lung adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used data from the National Cancer Center LungReal database, a multicenter, electronic health records-based database for patients undergoing surgery for lung cancer, from January 2014 to December 2021, with the last follow-up in December 2022. Patients were categorized based on histologic pattern of adenocarcinoma into 2 groups: lepidic without high-grade pattern, and high-grade or no lepidic pattern. The data analysis was performed from April to November 2025.

EXPOSURE: Lymph node dissection adherence or nonadherence with the 3 + 1 standard (3 N2 plus 1 N1 station) and the 6-station standard (the subcarinal plus 2 other N2 stations and 3 N1 stations).

MAIN OUTCOME AND MEASURE: Overall survival.

RESULTS: Of 35 265 patients screened, 27 191 participants (mean [SD] age, 58.3 [11.7] years; 16 280 female [59.9%] and 10 911 male [40.1%] individuals) from 19 centers were included; among them, 15 593 (57.3%) received lymph node dissection adherent with the 3 + 1 standard and 4023 (14.8%) with the 6-station standard. Among the group of 13 369 patients (49.2%) with adenocarcinoma of lepidic without high-grade pattern, no association was observed between survival and adherence with the 3 + 1 standard (hazard ratio [HR], 0.81; 95% CI, 0.57-1.15) or the 6-station standard (HR, 0.54; 95% CI, 0.26-1.13). Whereas, among the group of 13 822 patients (50.8%) with adenocarcinoma of high-grade or no lepidic pattern, adherence with the 3 + 1 standard (HR, 0.81; 95% CI, 0.69-0.95; absolute risk difference at 3-year, 1.2%; 95% CI, 0.2%-2.2%; E-value, 1.78) or the 6-station standard (HR, 0.61; 95% CI, 0.45-0.83; absolute risk difference at 3 years, 1.0%; 95% CI, 0.1%-1.9%; E-value, 2.67) was associated with a significant but small absolute survival benefit.

CONCLUSION AND RELEVANCE: In this cohort study, guideline-adherent nodal dissection was associated with small absolute survival benefit for patients with adenocarcinoma of high-grade or no lepidic pattern, but not for those with lepidic without high-grade pattern. These observational findings warrant prospective validation and should not be interpreted as causal.

PMID: 41538156

34. Cell Host Microbe. 2026 Jan 14;34(1):68-85.e13. doi:10.1016/j.chom2025.12.002. Epub 2025 Dec 30.

A CLOCK-targeting lncRNA induces trained immunity against tuberculosis.

Trained immunity confers innate immune memory via metabolic and epigenetic reprogramming, yet the intercellular mediators regulating this process in host defense remain largely elusive. Here, through plasma exosomal profiling of tuberculosis (TB)-resistant individuals, we identify a trained immunity-inducing long non-coding RNA (lncRNA), termed tuberculosisresister-derived CLOCK regulator 1 (TRCR1). Mechanistically, exosome-derived TRCR1 collaborates with the RNA-binding protein FXR2 to stabilize CLOCK mRNA by forming lncRNA-protein-mRNA complexes in monocytes, thus enhancing circadian regulator CLOCK expression and promoting CLOCK-mediated histone H3 acetylation (K9/K14) at immune gene promoters, ultimately establishing epigenetic memory-mediated antimicrobial activity. We further reveal that Mycobacterium tuberculosis (Mtb)-secreted protein MPT53 induces lung epithelial cells to release TRCR1-enriched exosomes. In mice, TRCR1 training strengthens host anti-Mtb immunity and improves Bacille Calmette-Guérin (BCG) vaccine efficacy. Collectively, our findings unveil an intercellular TRCR1-FXR2-CLOCK axis driving trained immunity at the lung-systemic immune interface, providing a strategy for refining BCG vaccination and preventing infectious diseases.

PMID: 41475336 [Indexed for MEDLINE]

35. Nat Biomed Eng. 2026 Jan 21. doi: 10.1038/s41551-025-01594-3. Online ahead of print.

Lung tumorous 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 tumor heterogeneity and resistance. Preclinical models that capture patient-specific factors are essential for personalizing treatment decisions. Here we show that matched lung tumorous and healthy lung organoids derived from patients provide a robust platform for studying therapy responses. The tumorous faithfully retained the molecular and histological identity of the original tumors, as confirmed by genomic, epigenetic 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, tumor-intrinsic resistance programmers. 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 tumors.

PMID: 41565786