CAR-T（CAR-T）细胞疗法在非肿瘤性疾病中的应用
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
预测实体瘤 CAR-T 治疗结局的混合多尺度模型
英文原题：A Hybrid Multiscale Model for Predicting CAR-T Therapy Outcomes in Solid Tumors.
查看英文原题
A Hybrid Multiscale Model for Predicting CAR-T Therapy Outcomes in Solid Tumors.
分数与星级只用于站内排序 —— 不代表疗效、安全性或个人适用性。
中文摘要
T 细胞在肿瘤内的分布（“肿瘤热度”）关键性地决定免疫治疗的成功。然而，尽管有众多策略来增强瘤内 T 细胞积聚——如多靶点 CAR-T 和联合方案——对 T 细胞-微环境相互作用的机制理解有限，制约了进展。为解决这一问题，我们开发了一个 3D 肿瘤微环境（TME）的生理机制模型，以评估 CAR-T 在环境波动和不同输注策略下的表现。该模型整合了关键的血管屏障（滚动、黏附、内皮抑制）和间质屏障（ECM 密度、代谢竞争、趋化因子敏感性）。
我们的模拟揭示，胶原密度和代谢竞争主导 CAR-T 疗效。增强血管黏附可改善浸润，但仍受胶原和代谢限制。内皮抑制显著降低肿瘤热度，而缓解内皮抑制则增强应答。全身输注比瘤内递送产生更高的肿瘤热度，但联合途径或降低胶原即使在致密肿瘤中也能恢复疗效。这一机制框架使得能够理性优化 CAR-T 策略。意义声明：CAR-T 细胞等免疫疗法的成功取决于其浸润并在实体瘤内持续存在的能力，然而调控这一过程的机制仍知之甚少。利用肿瘤微环境的机制性 3D 模型，我们定量剖析了血管和间质屏障——包括内皮抑制、胶原密度、代谢竞争和趋化因子信号——如何塑造 CAR-T 分布（“肿瘤热度”）。
我们的结果揭示，主导CAR-T 疗效的是基质和代谢限制，而非单纯的血管黏附。这一框架连接了分子、细胞和组织尺度的机制，为优化CAR-T 设计和递送策略以克服实体瘤耐药性提供了定量基础。
展开英文摘要原文
UNLABELLED: T cell distribution within tumors ("tumor hotness") critically determines immunotherapy success.
However, despite numerous strategies to enhance intratumoral T cell accumulation-such as multi-target CAR-Ts and combinatorial approaches-limited mechanistic understanding of T cell-microenvironment interactions has constrained progress.
To address this, we developed a physiological mechanistic model of the 3D tumor microenvironment (TME) to evaluate CAR-T performance under environmental fluctuations and different infusion strategies. The model integrates key vascular (rolling, adhesion, endothelial suppression) and interstitial (ECM density, metabolic competition, chemokine sensitivity) barriers.
Our simulations reveal that collagen density and metabolic competition dominate CAR-T efficacy. Enhancing vascular adhesion improves infiltration but remains limited by collagen and metabolism. Endothelial suppression markedly reduces tumor hotness, while its alleviation enhances response. Systemic infusion yields higher tumor hotness than intratumoral delivery, but combined routes or reduced collagen restore efficacy even in dense tumors. This mechanistic framework enables rational optimization of CAR-T strategies.
SIGNIFICANCE STATEMENT: The success of immunotherapies such as CAR-T cells depends on their ability to infiltrate and persist within solid tumors, yet the mechanisms that govern this process remain poorly understood. Using a mechanistic 3D model of the tumor microenvironment, we quantitatively dissected how vascular and interstitial barriers-including endothelial suppression, collagen density, metabolic competition, and chemokine cues-shape CAR-T distribution ("tumor hotness").
Our results reveal that stromal and metabolic constraints, rather than vascular adhesion alone, dominate CAR-T efficacy. This framework bridges molecular, cellular, and tissue-scale mechanisms, providing a quantitative foundation for optimizing CAR-T design and delivery strategies to overcome resistance in solid tumors.
论文信息
- 作者
- Nikmaneshi MR、Munn LL
- 文献类型
- 预印本
- 期刊
- bioRxiv : the preprint server for biology2025 Nov 18
- 原文标识
- PubMed 41332574 · DOI 10.1101/2025.11.17.688869