Background Lung cancer remains a major public health burden, with poor survival largely driven by late-stage diagnosis. With declining and very low smoking prevalence in Singapore at 4.7% in 2024 among 18-29-year-olds, questions arise about future screening efficiency, eligibility criteria, and the impact of smoking cessation, including tobacco elimination. Methods We developed a large-scale microsimulation model calibrated to real-world data, generating individual life histories, smoking trajectories, and disease progression for Singapore's 4.18 million residents to project smoking prevalence and lung cancer burden. We evaluated 271 low-dose computed tomography (LDCT) screening strategies (by age, gender, uptake, and frequency) under five tobacco control scenarios, from status quo to a complete smoking ban, between 2025 and 2050. Findings Under the status quo, all screening strategies were cost-effective relative to the 2024 GDP per capita threshold (~SGD 120,000). Among strategies with fewer than 10% overdiagnosis, annual screening of eligible ever-smokers aged 50-80 years was most life-saving, yielding 51,312 (95% uncertainty interval: 36,821-72,830) QALYs at a total cost of SGD 12.2 (9.7-16.1) billion. Adding an immediate smoking ban increased QALY gains by 2.8 (2.2-3.5) times while reducing the total cost by 23.3% (17.0%-30.0%). Extending eligibility to individuals with lower smoking exposure or a first-degree family history remained cost-effective. Interpretations Tobacco elimination yields substantial health and economic benefits, while well-designed risk-based LDCT screening of residual high-risk populations remains cost-effective, supporting a continued role for screening even in settings with declining smoking prevalence.

The authors have declared no competing interest.

This work was supported by the National Medical Research Council (NMRC) Population Health Research Grant - New Investigator Grant (MOH-001430-00 PHRG-NIG) and Population Health Metrics and Analytics project, funded by the Ministry of Health, Singapore.

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Ethical approval was obtained from the SingHealth Centralised Institutional Review Board for SP2 and the National University of Singapore Institutional Review Board for the remaining MEC1 studies. Population-level lung cancer data, including five-year incidence and mortality counts stratified by five-year age group, gender, ethnicity, and stage (where applicable), as well as stage-specific survival probabilities, were aggregated from de-identified individual-level records from the Singapore Cancer Registry, provided by the National Registry of Diseases Office (NRDO).

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