CT Screening Challenges Amid Rising Threat of Lung Cancer in Individuals Who Have Never Smoked

Lung cancer in individuals who have never smoked (LCINS) constitutes a growing global health challenge, accounting for 10%-25% of lung cancer cases and ranking as the fifth leading cause of cancer-related death worldwide. LCINS is especially common in East Asian women. LCINS arises from multiple nonsmoking-related risk factors, including secondhand smoke, air pollution, radon exposure, genetic susceptibility, and aging. LCINS exhibits unique biologic characteristics, with a predominance of adenocarcinoma, a high prevalence of actionable driver mutations (EGFR, ALK, ROS1), and a lower tumor mutational burden. Although chest low-dose CT (LDCT) screening has shown potential for early detection of LCINS, its widespread application in populations at low risk for developing lung cancer raises concerns about overdiagnosis, overtreatment, and radiation exposure, with mortality benefits yet to be demonstrated. Future screening strategies should focus on ensuring precise risk stratification, optimizing screening intervals, and minimizing potential harm. Incorporating demographic, clinical, genetic, and environmental data-potentially supported by artificial intelligence-may enable more personalized approaches. Given the indolent nature of many screen-detected LCINS, there is a need to shift the clinical mindset toward prioritizing active surveillance instead of immediate surgery. Overall, LDCT screening for LCINS requires careful balancing of potential benefits and harms, underscoring the need for tailored, evidence-based strategies.