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BackgroundImmune 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 abona fidetumor suppressor that is repressed in lung cancer to drive cancer and its chemo- and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement.MethodsHuman clinical samples and data were used to investigatePDLIM2genetic 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 administratedPdlim2expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs.ResultsPDLIM2repression 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.ConclusionsThese studies established a clinically applicable PDLIM2-based combination therapy with significantly improved efficacy for lung cancer and possibly other cold cancers.