Amato Luisa, De Rosa Caterina, Di Guida Gaetano, Sepe Filippo, Ariano Annalisa, Capaldo Sara, Ul Haq Faiz, Di Liello Alessandra, Tuccillo Concetta, Lucà Stefano, Franco Renato, De Rosa Viviana, Iommelli Francesca, Servetto Alberto, Ciardiello Fortunato, Della Corte Carminia Maria, Morgillo Floriana
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131, Naples, Italy.
Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138, Naples, Italy.
Cell Death Dis. 2025 Apr 13;16(1):286. doi: 10.1038/s41419-025-07636-7.
Immunotherapy has transformed the treatment landscape for non-small cell lung cancer (NSCLC), yet achieving lasting benefits remains a challenge. The resistance mechanisms to immunotherapy are complex, involving interactions between tumor cells and immune cells that are not fully understood. Metformin, an FDA-approved diabetes medication, shows promise in enhancing immunotherapy efficacy by boosting anti-tumor immune responses, although the underlying molecular pathways are still being investigated. This study utilized co-culture models of cancer and immune cells to explore the effects of combining metformin with anti-PD-1/PD-L1 therapies on the anti-tumor immune response in LKB1 mutant (LKB1mut) versus wild-type (LKB1wt) NSCLC cells, alongside peripheral blood immune cells from NSCLC patients. The transcriptomic profiles of LKB1mut and LKB1wt NSCLC cells were characterized via bulk RNA sequencing to understand gene expression changes induced by metformin. Patients with advanced-stage NSCLC provided peripheral blood mononuclear cells (PBMCs) for analysis. The study assessed metformin's impact both alone and in combination with anti-PD-1/PD-L1 agents on innate immune pathways. Results indicated that metformin activated the cGAS-STING pathway and interferons in PBMCs, enhancing their anti-tumor capabilities. Notably, immune cells treated with metformin and immunotherapy exhibited synergistic effects, significantly reducing colony formation in LKB1mut NSCLC cells. Additionally, monocytes from NSCLC patients showed decreased viability of NSCLC cells in co-culture, independent of LKB1 status, and shifted towards an anti-tumor M1 phenotype with combined treatment. These findings were supported by 3D co-culture models involving tumor spheroids and patient-derived organoids, highlighting a novel biological rationale for using metformin alongside immunotherapeutic agents to boost anti-tumor activity across various immune cell subsets derived from NSCLC patients.
免疫疗法已经改变了非小细胞肺癌（NSCLC）的治疗格局，但实现持久疗效仍然是一项挑战。免疫疗法的耐药机制很复杂，涉及肿瘤细胞与免疫细胞之间的相互作用，而这些相互作用尚未完全明确。二甲双胍是一种经美国食品药品监督管理局（FDA）批准的糖尿病药物，尽管其潜在的分子途径仍在研究中，但它有望通过增强抗肿瘤免疫反应来提高免疫疗法的疗效。本研究利用癌症细胞与免疫细胞的共培养模型，探讨二甲双胍与抗PD-1/PD-L1疗法联合应用对LKB1突变型（LKB1mut）与野生型（LKB1wt）NSCLC细胞以及NSCLC患者外周血免疫细胞抗肿瘤免疫反应的影响。通过大量RNA测序对LKB1mut和LKB1wt NSCLC细胞的转录组图谱进行表征，以了解二甲双胍诱导的基因表达变化。晚期NSCLC患者提供外周血单核细胞（PBMC）用于分析。该研究评估了二甲双胍单独使用以及与抗PD-1/PD-L1药物联合使用对固有免疫途径的影响。结果表明，二甲双胍激活了PBMC中的cGAS-STING途径和干扰素，增强了它们的抗肿瘤能力。值得注意的是，用二甲双胍和免疫疗法处理的免疫细胞表现出协同效应，显著减少了LKB1mut NSCLC细胞中的集落形成。此外，NSCLC患者的单核细胞在共培养中显示出NSCLC细胞活力下降，与LKB1状态无关，并且联合治疗使其向抗肿瘤M1表型转变。这些发现得到了涉及肿瘤球体和患者来源类器官的三维共培养模型的支持，突出了将二甲双胍与免疫治疗药物联合使用以增强来自NSCLC患者的各种免疫细胞亚群的抗肿瘤活性的新生物学原理。
