<p>Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality and often shows poor responsiveness to immune checkpoint therapies due to persistent tumor-induced immunosuppression. Programmed Death-Ligand 1 (PD-L1) and Indoleamine 2,3-dioxylase 1 (IDO1) are critical inhibitory regulators of anti-tumor immunity and represent important therapeutic targets in NSCLC. In this study, a structure-based computational strategy was employed to identify small molecules with inhibitory activity against both PD-L1 and IDO1. A library of approximately 61,000 compounds with reported anticancer activity was subjected to virtual screening. Molecular docking was performed using AutoDock, followed by systematic filtering based on binding affinity, key inhibitory interactions, and physicochemical drug-likeness criteria. Top-ranked compounds were further evaluated through MM/GBSA binding free energy calculations and molecular dynamics simulations to assess binding stability and inhibitory interaction persistence within the active or functional sites of PD-L1 and IDO1. Five compounds Vindoline, Riboflavin, Ascorbic acid, Kaempferol, and Duboisine exhibited strong binding affinities and stable inhibitory interactions with both targets throughout the simulations. These findings suggest that the identified small molecules may effectively inhibit PD-L1 and IDO1, thereby potentially alleviating immune suppression in NSCLC. The study provides a rational in silico framework for the discovery and preclinical development of small-molecule inhibitors targeting immune resistance mechanisms.</p> Graphical Abstract <p></p>