免疫检查点抑制剂（ICIs）及其与其他治疗方法（如化疗）的联合治疗，在大多数癌症患者中都存在失败的情况。我们此前发现，PDZ-LIM结构域含蛋白2（PDLIM2）是一种真正的肿瘤抑制因子，在肺癌中被抑制以驱动癌症及其化疗和免疫治疗的耐药性，为肺癌治疗的改进提供了新的靶点。通过使用人类临床样本和数据，我们研究了PDLIM2在肺癌中的遗传和表观遗传变化。通过使用一个忠实再现难治性人类肺癌的内源性小鼠肺癌模型以及临床可行的纳米递送系统，我们研究了以纳米颗粒（nanoPDLIM2）封装的PDLIM2表达质粒的全身给药方式的治疗有效性、作用机制和安全性，以及其与PD-1抗体和化疗药物的联合应用。PDLIM2在人类肺癌中的抑制涉及基因删除和启动子甲基化。纳米PDLIM2显示出低毒性、高肿瘤特异性、抗肿瘤活性，并显著改善了抗PD-1和化疗药物的疗效，在60%的小鼠中实现了完全的肿瘤缓解，剩余小鼠中肿瘤显著减小，通过此三种疗法的联合应用。在机制上，纳米PDLIM2增加了肿瘤细胞的重要组织相容性复合物I类（MHC-I）的表达，抑制了多药耐药1（MDR1）的诱导，以及细胞核中的Rela和stat 3以及存活基因（Bcl-xl和cyclin D1）；同时，它也增强了淋巴细胞对肿瘤的浸润和激活，使寒冷的肿瘤变热，对ICIs敏感，并使其对化疗药物变得脆弱。这些研究建立了一种基于PDLIM2的组合疗法，可在肺癌和可能的其他冷瘤中显著提高疗效，并具有临床应用价值。

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 bona fide tumor 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.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.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.These studies established a clinically applicable PDLIM2-based combination therapy with significantly improved efficacy for lung cancer and possibly other cold cancers.