Andreou Tereza, Neophytou Constantina, Kalli Maria, Mpekris Fotios, Stylianopoulos Triantafyllos
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
Cancer Genetics, Therapeutics & Ultrastructural Pathology Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Front Immunol. 2025 Sep 3;16:1638186. doi: 10.3389/fimmu.2025.1638186. eCollection 2025.
Whilst chimeric antigen receptor (CAR) T cell therapy has emerged as a revolutionary immunotherapeutic approach for hematological malignancies in recent years, several challenges remain to potentiate the efficacy of CAR T cell therapies for solid tumors. Here, we focus on the obstacles posed by the tumor microenvironment that hinder the effective trafficking, infiltration and precise tumor targeting by engineered cells. We discuss how the tumor microenvironment presents a physical barrier that needs to be surpassed for effective cell therapies and ongoing efforts in designing innovative CAR T cell therapies with enhanced tumor-targeting precision, improved stability, and overcoming on-target off-tumor toxicity are presented. We focus on recent advances in clinical and preclinical settings to reprogram the immunosuppressive tumor microenvironment, including stroma and blood vessel normalization strategies that can be leveraged to improve the tumor-homing and tumor-targeting potential of engineered therapeutic cells for immuno-oncology applications. As the endeavors for innovative CAR designs continue, we are entering an exciting era in the field of personalized cell therapies offering renewed hope to patients with hard-to-treat solid tumors.
近年来，嵌合抗原受体（CAR）T细胞疗法已成为治疗血液系统恶性肿瘤的一种革命性免疫治疗方法，但要提高CAR T细胞疗法对实体瘤的疗效仍面临诸多挑战。在此，我们聚焦肿瘤微环境所带来的障碍，这些障碍阻碍了工程细胞的有效运输、浸润以及对肿瘤的精准靶向。我们讨论了肿瘤微环境如何构成一种物理屏障，有效细胞疗法需要克服这一屏障，并且介绍了目前在设计创新型CAR T细胞疗法方面所做的努力，这些疗法具有更高的肿瘤靶向精准度、更好的稳定性，并能克服靶向非肿瘤毒性。我们关注临床和临床前环境中在重新编程免疫抑制性肿瘤微环境方面的最新进展，包括可用于改善工程治疗细胞的肿瘤归巢和肿瘤靶向潜力的基质和血管正常化策略，以用于免疫肿瘤学应用。随着创新型CAR设计的不断努力，我们正进入个性化细胞疗法领域的一个激动人心的时代，为难以治疗的实体瘤患者带来了新的希望。
