The tumor microenvironment (TME) and its major component tumor-associated macrophages (TAM) play a pivotal role in the development of non-small cell lung cancer (NSCLC). An epigenetic drug-based combinatory therapeutic strategy was proposed and a deformable liposome system (D-Lipo) was developed for vorinostat and simvastatin codelivery for remodeling the TME. The application of deformable liposomes in systemic cancer drug delivery has been underexplored and its potential in cancer therapy is largely unknown. This work revealed that D-Lipo exhibited an enhanced intratumor infiltration ability. The proposed therapeutic strategy was characterized by a chemo-free regimen and TME remodeling function. D-Lipo efficiently inhibited the growth of the xenografted lung tumor. The anti-tumor mechanisms involved the repolarization of TAM from the M2 to M1 phenotype, anti-angiogenesis, and the consequent TME remodeling. As a result, the amounts of the anti-tumor M1 macrophages and the cytotoxic CD8+ T cells increased, while the amounts of the pro-tumor M2 macrophages and regulatory T cells (Tregs) reduced. It provides a promising avenue for epigenetic drug-based combination therapy for treating solid tumors.