肿瘤细胞治疗研究
英文原题：Immune cell-based therapies for solid tumors, current challenges and therapeutic advances.
实体瘤仍难以治疗，原因在于抗原异质性、限制免疫细胞迁移的物理屏障以及深度免疫抑制的肿瘤微环境（TME）。
实体瘤治疗仍十分困难，原因包括抗原异质性、阻碍免疫细胞迁移的物理屏障，以及强烈的免疫抑制性肿瘤微环境（TME）。过去十年，癌症免疫治疗借助多种创新策略取得显著进步，包括巨噬细胞重编程和CAR-巨噬细胞、树突状细胞（DC）疫苗、自然杀伤（NK）及自然杀伤T（NKT）细胞疗法、TIL（肿瘤浸润淋巴细胞）疗法、TCR工程化及CAR-T细胞、新兴B细胞工程，以及细胞来源的细胞外囊泡（EV）。本文总结各类疗法与TME的相互作用，介绍关键临床里程碑（如FDA于2024年批准用于黑色素瘤的TIL产品），并概述旨在克服耐药和毒性的生物工程策略，包括多抗原靶向、细胞因子赋能、迁移引导信号和安全开关。综述也介绍基于EV的无细胞策略，这类方法保留肿瘤特异性，同时可能改善安全性和生产能力。最后，文章讨论标准化生产、靶向肿瘤同时损伤正常组织的效应及持久性不足等障碍，并提出与免疫检查点阻断、放疗和靶向药物进行合理联合。本文将免疫细胞疗法定位为快速成熟、可改变实体瘤治疗格局的策略。
Solid tumors remain difficult to treat due to antigen heterogeneity, physical barriers that limit immune-cell trafficking, and a profoundly immunosuppressive tumor microenvironment (TME). Over the past decade, cancer immunotherapy advanced considerably through innovative strategies, including macrophage reprogramming and CAR-macrophages, dendritic-cell (DC) vaccines, natural killer (NK) and natural killer T (NKT) cell approaches, tumor-infiltrating lymphocyte (TIL) therapy, TCR-engineered and CAR-T cells, emerging B-cell engineering, and cell-derived extracellular vesicles (EVs). Here we summarize how each modality interacts with the TME, highlight key clinical milestones (e.g., FDA approval of a TIL product for melanoma in 2024), and outline bioengineering strategies-multi-antigen targeting, cytokine armoring, trafficking cues, and safety switches-that aim to overcome resistance and toxicity. We also review EV-based, cell-free strategies that retain tumor specificity with potentially improved safety and manufacturability. Finally, we discuss remaining barriers-standardized manufacturing, on-target/off-tumor effects, limited persistence-and propose rational combinations with checkpoint blockade, radiotherapy, and targeted agents. This overview positions immune cell-based therapy as a rapidly maturing, transformative approach for solid tumors.
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