Abstract

Non-small cell lung cancer (NSCLC) remains a major global health challenge, with limited therapeutic success due to drug resistance and the immunosuppressive tumor microenvironment (TME). This study explores a novel strategy to overcome acquired resistance to immunotherapy in phosphoinositide 3-kinase (PI3K)-mutated NSCLC. Tumor-derived exosomes (T-exo) were modified with the tumor-targeting peptide TMTP1 and loaded with Ginsenoside Rb1 (Rb1) via electroporation to develop peptide-modified Rb1@T-exo. This innovative delivery system demonstrated enhanced tumor-targeting ability and improved stability and bioavailability of Rb1. Both in vitro and in vivo experiments revealed that Rb1@T-exo effectively suppressed tumor growth and metastasis, significantly inhibited the PI3K/AKT/mTOR signaling pathway, and remodeled the immune microenvironment by promoting M1 macrophage polarization and enhancing CD8⁺ T cell proliferation and cytotoxicity. Transcriptomic and bioinformatic analyses identified key differentially expressed genes (DEGs) and pathways associated with resistance reversal, including the PI3K/AKT/mTOR and PD-1/PD-L1 pathways. Moreover, Rb1@T-exo synergized with immune checkpoint blockade therapy, demonstrating potential as a dual therapeutic approach. This study highlights the potential of peptide-modified Rb1@T-exo as a targeted therapeutic platform for overcoming immunotherapy resistance in PI3K-mutated NSCLC and provides a promising direction for future anti-tumor therapies.