Methods: Human clinical samples and data were used to investigate PDLIM2 genetic and epigenetic changes in
lung cancer. Using an endogenous mouse
lung cancer model faithfully recapitulating refractory human
lung cancer and a clinically feasible
nano-delivery system, we investigated the therapeutic efficacy, action mechanism, and safety of systemically administrated Pdlim2 expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs.
Results: PDLIM2 repression in human
lung cancer involves both genetic deletion and promoter methylation. NanoPDLIM2 showed low toxicity, high
tumor specificity, antitumor activity, and greatly improved the efficacy of anti-PD-1 and chemotherapeutic drugs, with complete
tumor remission in 60% of mice and substantial
tumor reduction in the remaining mice by the combination of three
therapies. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction, nuclear Rela and stat 3, and survival genes (Bcl-xl and cycline D1) in
tumor cells; meanwhile it enhanced lymphocyte
tumor infiltration and activation, thus turning the cold
tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs.
Conclusions: