Cancer stem cells (CSCs), harboring stem cell-like properties involving self-renewal and aberrant differentiation potential, have been known to be one of the determining factors that contribute to therapeutic resistance and tumor recurrence. However, much remains to be understood about the reprogramming network leading to the generation of CSCs driven by chemotherapy. In this study, guided by bioinformatics study, we uncover and provide deeper insight into the CSC enrichment mechanism driven by cisplatin (CDDP) treatment. We discover that CDDP can repopulate the level of CSC by activating AKT1 oncogenic pathway that is further enhanced by COX-2 inflammatory signaling. Simultaneously blocking these two pathways can synergistically restrain the number of CSCs. Under the guidance of a series of advanced hierarchical computational modeling, including molecular docking, molecular dynamics (MD) simulation and binding free energy analysis, MK-2206 is selected as the AKT1 inhibitor to achieve optimal codelivery of CDDP, MK-2206 and 5-ASA (COX-2 inhibitor) through the use of 5-ASA-derivatized dual functional immunostimulatory nanocarrier (PASA). This triple combination (PASA/CDDP/MK-2206) significantly reduces tumor burden in both orthotopic and metastatic lung cancer models. Mechanistic studies show that this improved therapeutic activity is due to elimination of CSCs and reversal of the immunosuppressive tumor microenvironment. Our study suggests that PASA/CDDP/MK-2206 may represent a simple and effective lung cancer therapy via reversing CSCs-associated chemoresistance.