Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2.

Background: Immune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as a Methods: Human clinical samples and data were used to investigate Results: PDLIM2 repression in human lung cancer involves both genetic deletion and epigenetic alteration. 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 most mice and substantial tumor reduction in the remaining mice by their triple combination. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction and survival genes and other tumor-related genes expression in tumor cells, and enhanced lymphocyte tumor infiltration, turning the cold tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs and activated tumor-infiltrating lymphocytes (TILs) including those unleashed by ICIs. Conclusions: These studies established a clinically applicable PDLIM2-based combination therapy with great efficacy for lung cancer and possibly other cold cancers.