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.
恒定自然杀伤T（iNKT）细胞是一类独特的T细胞亚群，连接先天性与适应性免疫，通过细胞因子分泌、直接细胞毒性作用以及招募CD8+T细胞和NK细胞等免疫效应细胞，展现出强大的抗肿瘤特性。尽管具有治疗潜力，但以调节性T细胞、髓源性抑制细胞（MDSCs）和肿瘤相关巨噬细胞（TAMs）为特征的免疫抑制性肿瘤微环境（TME）限制了iNKT细胞的疗效。患者来源类器官（PDO）平台为解析这些复杂相互作用、评估重振iNKT细胞在TME中功能的策略提供了创新模型。PDO能高度模拟原发肿瘤的遗传、表型和结构特征，从而实现对肿瘤-免疫动态的研究。将iNKT细胞整合至PDO体系，为研究CD1d介导的相互作用、α-GalCer等糖脂类似物驱动的Th1偏向性免疫应答，以及免疫检查点抑制剂等联合疗法提供了强大平台。此外，PDO系统可评估代谢调控（如减少乳酸积累或靶向谷氨酰胺通路）对增强iNKT细胞活性的影响。器官芯片系统、CRISPR-Cas9基因编辑和多组学分析等新兴技术，进一步拓展了PDO-iNKT平台在个体化免疫治疗研究中的潜力。尽管iNKT细胞在PDO中的应用尚处早期阶段，这些系统在连接临床前研究与临床转化方面前景广阔。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体化医疗提供了变革性途径。
Patient-Derived Organoid Models for NKT Cell-Based Cancer Immunotherapy
肿瘤(癌症)患者之家