成纤维细胞激活蛋白靶向近红外光免疫疗法耗竭免疫抑制性肿瘤相关成纤维细胞并重塑局部肿瘤免疫。

BACKGROUND: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a critical role in tumor immunosuppression. However, targeted depletion of CAFs is difficult due to their diverse cells of origin and the resulting lack of specific surface markers. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that leads to rapid cell membrane damage. METHODS: In this study, we used anti-mouse fibroblast activation protein (FAP) antibody to target FAP CAFs (FAP-targeted NIR-PIT) and investigated whether this therapy could suppress tumor progression and improve tumor immunity. RESULTS: FAP-targeted NIR-PIT induced specific cell death in CAFs without damaging adjacent normal cells. Furthermore, FAP-targeted NIR-PIT treated mice showed significant tumor regression in the CAF-rich tumor model accompanied by an increase in CD8 tumor infiltrating lymphocytes (TILs). Moreover, treated tumors showed increased levels of IFN-γ, TNF-α, and IL-2 in CD8 TILs compared with non-treated tumors, suggesting enhanced antitumor immunity. CONCLUSIONS: Cancers with FAP-positive CAFs in their TME grow rapidly and FAP-targeted NIR-PIT not only suppresses their growth but improves tumor immunosuppression. Thus, FAP-targeted NIR-PIT is a potential therapeutic strategy for selectively targeting the TME of CAF tumors.

背景：肿瘤微环境（TME）中的癌症相关成纤维细胞（CAFs）在肿瘤免疫抑制中发挥着关键作用。然而，由于其起源细胞的多样性以及缺乏特异性表面标志物，靶向耗竭 CAFs 具有一定的难度。近红外光免疫治疗（NIR-PIT）是一种新型的癌症治疗方法，可导致细胞膜迅速损伤。

方法：在本研究中，我们使用抗鼠成纤维细胞激活蛋白（FAP）抗体靶向 FAP-CAFs（FAP 靶向 NIR-PIT），并研究了这种治疗方法是否可以抑制肿瘤进展并改善肿瘤免疫。

结果：FAP 靶向 NIR-PIT 可特异性诱导 CAFs 死亡，而不会损伤相邻的正常细胞。此外，在富含 CAFs 的肿瘤模型中，FAP 靶向 NIR-PIT 治疗的小鼠表现出显著的肿瘤消退，同时 CD8 肿瘤浸润淋巴细胞（TIL）增加。此外，与未治疗的肿瘤相比，治疗后的肿瘤中 CD8 TIL 中的 IFN-γ、TNF-α 和 IL-2 水平增加，表明抗肿瘤免疫增强。

结论：TME 中存在 FAP 阳性 CAFs 的癌症生长迅速，FAP 靶向 NIR-PIT 不仅能抑制其生长，还能改善肿瘤免疫抑制。因此，FAP 靶向 NIR-PIT 是一种针对 CAF 肿瘤 TME 的潜在治疗策略。