Palacios Pablo A, Flores Iván, Cereceda Lucas, Otero Francisco F, Müller Marioly, Brebi Priscilla, Contreras Héctor R, Carreño Leandro J
Millennium Institute on Immunology and Immunotherapy, Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile.
Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, Santiago 8350499, Chile.
Cancers (Basel). 2025 Jan 26;17(3):406. doi: 10.3390/cancers17030406.
Invariant Natural Killer T (iNKT) cells are a unique subset of T cells that bridge innate and adaptive immunity, displaying potent anti-tumor properties through cytokine secretion, direct cytotoxicity, and recruitment of immune effector cells such as CD8 T cells and NK cells. Despite their therapeutic potential, the immunosuppressive tumor microenvironment (TME), characterized by regulatory T cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs), limits iNKT cell efficacy. Patient-derived organoid (PDO) platforms provide an innovative model for dissecting these complex interactions and evaluating strategies to reinvigorate iNKT cell functionality within the TME. PDOs closely mimic the genetic, phenotypic, and structural characteristics of primary tumors, enabling the study of tumor-immune dynamics. Integrating iNKT cells into PDOs offers a robust platform for investigating CD1d-mediated interactions, Th1-biased immune responses driven by glycolipid analogs like α-GalCer, and combination therapies such as immune checkpoint inhibitors. Additionally, PDO systems can assess the effects of metabolic modulation, including reducing lactic acid accumulation or targeting glutamine pathways, on enhancing iNKT cell activity. Emerging innovations, such as organoid-on-a-chip systems, CRISPR-Cas9 gene editing, and multi-omics approaches, further expand the potential of PDO-iNKT platforms for personalized immunotherapy research. Although the application of iNKT cells in PDOs is still undeveloped, these systems hold immense promise for bridging preclinical studies and clinical translation. By addressing the challenges of the TME and optimizing therapeutic strategies, PDO-iNKT platforms offer a transformative avenue for advancing cancer immunotherapy and personalized medicine.
不变自然杀伤T（iNKT）细胞是T细胞的一个独特亚群，它连接先天性免疫和适应性免疫，通过细胞因子分泌、直接细胞毒性以及募集免疫效应细胞（如CD8 T细胞和NK细胞）展现出强大的抗肿瘤特性。尽管它们具有治疗潜力，但以调节性T细胞、髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）为特征的免疫抑制性肿瘤微环境（TME）限制了iNKT细胞的功效。患者来源类器官（PDO）平台为剖析这些复杂的相互作用以及评估在TME中恢复iNKT细胞功能的策略提供了一个创新模型。PDO紧密模拟原发性肿瘤的遗传、表型和结构特征，能够研究肿瘤-免疫动力学。将iNKT细胞整合到PDO中为研究CD1d介导的相互作用、由α-GalCer等糖脂类似物驱动的Th1偏向性免疫反应以及免疫检查点抑制剂等联合疗法提供了一个强大的平台。此外，PDO系统可以评估代谢调节（包括减少乳酸积累或靶向谷氨酰胺途径）对增强iNKT细胞活性的影响。诸如芯片上类器官系统、CRISPR-Cas9基因编辑和多组学方法等新兴创新进一步扩展了PDO-iNKT平台在个性化免疫治疗研究中的潜力。尽管iNKT细胞在PDO中的应用仍未充分开发，但这些系统在弥合临床前研究和临床转化方面具有巨大前景。通过应对TME的挑战并优化治疗策略，PDO-iNKT平台为推进癌症免疫治疗和个性化医学提供了一条变革性途径。
